Session 1,
Chemical biology of the epigenetic signals and players (Morning, 20 April)

Guoliang Xu,Ph.D


Dr.Guoliang Xu obtained his Ph.D from the Max Planck Institute for Molecular Genetics & Technical University Berlin, Germany in 1993. He worked at the National University of Singapore 1994-1995, and then at Columbia University 1995-2001. Since 2001, Dr. Xu is a Principal Investigator of Institute of Biochemistry and Cell Biology, CAS in China. His research focuses on DNA methylation/modifications, stem cells and epigenetic reprogramming. He won the One-Hundred-Talents Award of the Chinese Academy of Sciences (2001) and Distinguished Young Investigator Award from China NSF (2002).

DNA Oxidation towards Totipotency in Mammalian Development
Sperm and eggs carry distinctive epigenetic modifications that are adjusted by reprogramming following fertilization. The paternal genome undergoes active DNA demethylation before the first mitotic division. The biological significance and mechanisms of paternal epigenome remodeling have remained unclear. We find that, within mouse zygotes, oxidation of occurs in the paternal genome, changing 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC). In Tet3-deficient zygotes from conditional knockout mice, the conversion of 5mC into 5hmC fails to occur. Thus, the loss of 5mC in the paternal genome in zygotes is caused by its conversion to 5hmC mediated by Tet3. Deficiency of Tet3 also impedes demethylation at the paternal copy of genes such as Oct4 and Nanog and delays the subsequent reactivation of Oct4 in early embryos. Heterozygous mutant embryos lacking maternal Tet3 suffer increased developmental failures, with female mice depleted of Tet3 in the germ line displaying severely reduced fecundity. Importantly, oocytes lacking Tet3 also show impaired reprogramming of injected somatic cell nuclei. We conclude that Tet3-mediated DNA oxidation is essential for epigenetic reprogramming in the early embryo following natural fertilization, as well as for the reprogramming of somatic cell nuclei during animal cloning.  

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Rui-Ming Xu, Ph.D


Rui-Ming Xu is an Investigator and Deputy Director of Institute of Biophysics, Chinese Academy of Sciences in Beijing. He received his Bachelor degree in physics from Zhejiang University in 1984, and Ph.D. degree in physics from Brandeis University in 1990. He then worked as a postdoctoral fellow in physics with Nobel Laureates Steven Weinberg at University of Texas in Austin, and Chen Ning Yang at SUNY at Stony Brook from 1989 to 1993. In 1993 he moved to Cold Spring Harbor Laboratory (CSHL) and changed his research area to structural biology. From 1996 to 2005, he rose thorough the ranks from assistant, associate to full professor at CSHL. In 2006 he moved to the Skirball Institute of Biomolecular Medicine at NYU school of Medicine as a tenured professor. He has been with the Institute of Biophysics in Beijing since moving back to China at the end of 2008.

Dr. Xu’s research interest has been on structural studies of histone modification enzymes, structural basis for recognition of histone modifications, and the molecular mechanisms of the assembly and maintenance of higher order chromatin structure. He is credited with the determination of the first NAD-dependent deacetylase structure, the structures of a number of prototypical histone methyltransferases, and the recognition modes of methylated histone tails by Tudor domain proteins. He currently serves on the Editorial Boards of Genes & Development and BBA-Gene Regulatory Mechanisms. 

Structure of a CENP-A-Histone H4 Heterodimer in Complex with Chaperone HJURP
Hao Hu1,2, Yang Liu1, Mingzhu Wang1, Junnan Fang1,2, Hongda Huang3, Na Yang1, Yanbo Li1, Jianyu Wang3, Xuebiao Yao3, Yunyu Shi3, Guohong Li1, and Rui-Ming Xu1
1National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China; 2Graduate University of Chinese Academy of Sciences, 19A Yuquan Road, Beijing 100049, China; 3Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, China
In higher eukaryotes, the centromere is epigenetically specified by the histone H3 variant CENP-A. Deposition of CENP-A to the centromere requires histone chaperone HJURP, but the molecular mechanism by which CENP-A is specifically recognized remains poorly understood. We have determined a 2.6 Å structure of the CENP-A binding domain (CBD) of HJURP with CENP-A and histone H4. The structure shows that HJURP CBD disrupts the CENP-A-H4 tetramer, and binds a hetrodimer of CENP-A and histone H4. The C-terminal -sheet domain of HJURP CBD caps the DNA-binding region of the histone heterodimer, preventing it from spontaneous association with DNA. Our analysis also discovered a novel site outside of the CATD domain of CENP-A that is crucial for distinguishing it from histone H3 in its ability to bind HJURP. These findings provide key information for specific recognition of CENP-A and mechanistic insights into the process of centromeric chromatin assembly.

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Xuebiao Yao, Ph.D

(An hui,China)

Dr. Xuebiao Yao graduated from the University of California at Berkeley in 1995 and carried out a postdoctoral fellowship with Dr. Don Cleveland at Ludwig Institute for Cancer Research in San Diego. He joined in the faculty of the University of Wisconsin-Madison as an Assistant Professor in 1997. Dr. Yao returned to China as Cheung Kong Scholar in 1999 and headed the Laboratory of Cellular Dynamics in the University of Science & Technology of China. His main research focus is to delineate the molecular society of mammalian kinetochore during cell division using a combination of functional proteomics, biophotonics, chemical biology and computational biology. Among many honors and affiliated duties, Dr. Yao serves as editors for Journal of Biological Chemistry, Cell Research and Journal of Molecular Cell Biology. He is the Director for Anhui Key Laboratory for Cellular Dynamics and Chemical Biology. Current research interests in his laboratory center on the epigenetic regulation of centromere plasticity and chemical biology of mitosis

Functional assembly of CENP-S and CENP-X tetrameric complex is essential for accurate chromosome segregation in mitosis.
Lingluo Chu, Changjiang Jin, Yuyong Tao, Maikun Teng, and Xuebiao Yao
University of Science & Technology of China, Hefei, China 230027
Chromosome movements in mitosis are orchestrated by dynamic interactions between spindle microtubules and the kinetochore, a multiprotein complex assembled onto centromeric DNA of the chromosome. The prime candidate for specifying centromere identity is the array of nucleosomes assembled with CENP-A. Our recent structural analyses of CENP-S and CENP-X complex revealed that CENP-S and CENP-X exhibit typical histone-fold structures and assemble as a functional tetramer (Tao et al., Nature Comms. 2012). Perturbation of CENP-S interaction with CENP-X prevents their functional assembly onto centromere and kinetochore plasticity. Interestingly, inhibition of CENP-X dimerization by point mutation also inhibits localization of CENP-X to the centromere and effects a chronic mitotic arrest. High-resolution microscopic imaging analyses reveal that CENP-S/X complex is required for organizing a stable bi-oriented microtubule kinetochore attachment that is essential for faithful chromosome segregation in mitosis. Currently, we are investigating the temporal dynamics of CENP-S and CENP-X complex assembly during mitosis.

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Yi Zhang, Ph.D

(Chapel Hill, USA)

Yi Zhang is an Investigator of the Howard Hughes Medical Institute and a Kenan Distinguished Professor at the Dept. of Biochemistry & Biophysics of the University of North Carolina at Chapel Hill, USA. He received his B.S. in Biophysics from China Agricultural University, and his Ph.D. in Molecular Biophysics from the Florida State University, Tallahassee in 1995. He was trained with Danny Reinberg as a postdoc working on the Sin3a and the NuRD histone deacetylase complexes at the Robert Wood Jonhson Medical School. He joined the faculty of the University of North Carolina at Chapel Hill in 1999. Dr. Zhang’s research has been focused on the identification and characterization of various histone and DNA modifying enzymes that include histone deacetylases, histone methyltransferase, histone ubiquitin E3 ligases, histone demethylases, and 5mC dioxygenases. His long term goal is to understand the role of these enzymes in normal development and how dysfunction of these enzymes contribute to various diseases.

Mechanism and function of Tet-mediated 5mC oxidation
Yi Zhang
Howard Hughes Medical Institute, and Departmement of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Epigenetic modifications play important roles in diverse biological processes that range from regulation of gene expression, embryonic development, stem cell reprogramming, and human diseases such as cancers. One of the epigenetic modifications is DNA methylation. Although enzymes responsible for DNA methylation have been well characterized, enzymes that responsible for active DNA demethylation in mammalian cells have remained elusive. Recent studies have demonstrated that a novel family of proteins Tet1-3 have the capacity to convert 5mC to 5hmC, 5fC, and 5caC raising the possibility that DNA demethylation may be initiated through Tet-catalyzed oxidation. In my talk, I will present our recent findings with regard to the mechanism and biological function of Tet-catalyzed 5mC oxidation.

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Shimin Zhao, Ph.D.


Shimin Zhao is a tenured Professor in Institutes of Biomedical Sciences, School of Life sciences, Fudan University, China. He received his B.S. in Chemistry from the Peking Normal University, Beijing, China in 1988, and his Ph.D. in Molecular Biology from the Department of Biochemistry, Purdue University,  West Lafayette, USA in 2000. Following brief industrial appointments in Proctor & Gamble, USA and Life Sciences Inc., USA, from 2000-2005, he joined the faculty of  Fudan University as an associate professor in 2006, he was promoted to full professor in 2009. Dr. Zhao’s research is focused on metabolism regulation and human diseases. His recent work led to the discovery of regulation of metabolism by metabolic enzymes acetylation, and to the findings that metabolites play critical roles in epigenetic regulation. Dr. Zhao’s lab utilizes biochemical, molecular biological and proteomic approaches to decipher the biochemical roles of metabolic enzymes modifications and the biochemical nature of how metabolites regulate epigenetic processes.  He has been appointed as Principle Investigator of National Basic Research Program (Protein) of China (2012-2016) in 2011

Metabolism regulation and human diseases
Institutes of Biomedical Sciences, School of Life Sciences, Fudan University,
Shanghai, P.R. China, 200032
Like proteins, metabolites comprise the vast majority of cellular components. They present in a broad range of cellular concentrations and participate in a wide variety of biochemical and regulatory functions. As regulators of protein function, metabolites can act globally to control many proteins or specifically target a limited number of proteins. -ketoglutarate (KG) and its structural analogous metabolites are closely related to epigenetic regulations. Activities of key epigenetic regulation enzymes, such as histone demethylases and DNA demethylation enzymes, are either KG dependent or competitively inhibited by KG analogs. Moreover, homocysteine, a folic acid pathway metabolite, has impact on epigenetics due to homocysteinylation on lysine residues in histones thus antagonize acetylation and methylation. These findings suggest that metabolites, besides being energy source and building blocks of cells, are likely important regulators of epigenetics. These findings also help us to understand the basis of an old saying “you are what you eat”.

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Hongjun Song, Ph.D

(Baltimore, USA)

Hongjun Song Hongjun Song, Ph.D. is Professor of Neurology and Neuroscience and Director of the Stem Cell Biology Program in the Institute for Cell Engineering at the Johns Hopkins University School of Medicine. Dr. Song received his B.S. from Peking University in China, M.A. from Columbia University and Ph.D. from University of California at San Diego. After postdoctoral training with Drs. Charles F. Stevens and Fred H. Gage at the Salk Institute, he established his own laboratory at Johns Hopkins University in 2003. Dr. Song's laboratory works on plasticity in the adult brain with a focus on adult neural stem cells and epigenetic DNA modifications. Using an integrated approach, Dr. Song's laboratory has identified both intrinsic and extrinsic mechanisms that regulate behaviors of multipotent adult neural stem cells and govern synaptic integration of newborn neurons in the adult brain in vivo. In addition, Dr. Song's laboratory has identified signal pathways involved in active DNA demethylation in the mammalian brain. Dr. Song has won several awards, including the Klingenstein Fellowship Awards in the Neuroscience, McKnight Scholar Award, Inaugural Young Investigator Award of the Chinese Biological Investigators Society, Young Investigator Award from the Society for Neuroscience, NARSAD Independent Investigator Award, and Rising Star Award from International Mental Health Research Organization. He has been a member of the Faculty of 1000 Biology and serving on the editorial board for several journals.

Neuronal Activity-Induced Changes of DNA Methylation Landscape in the Adult Brain
Epigenetic modifications of chromatin molecules, including the genomic DNA and histone proteins, play critical roles in orchestrating transcriptomes of all cell types and their developmental potentials. Emerging evidence suggests important roles for epigenetic regulation in activity-dependent brain functions, including synaptic plasticity, learning and memory, circadian rhythm, drug addiction, and adult neurogenesis. Recent studies have further implicated critical roles of DNA methylation changes in neural plasticity. Our early studies have shown that neuronal stimulation induces DNA demethylation at specific promoters of brain-derived neurotrophic factor and fibroblast growth factor 1 in a Gadd45b- and TET1-dependent fashion in the adult mouse dentate gyrus (Ma et al. Science 2009; Guo et al. Cell 2011). Using a next-generation sequencing-based method for genome-wide analysis at a single-nucleotide resolution, we recently showed that 1.4% of all CpGs measured exhibit rapid active demethylation or de novo methylation in adult mouse dentate granule neurons in vivo before and after synchronous neuronal activation (Guo et al. Nat. Neurosci. 2011). These activity-modified CpGs exhibit a broad genomic distribution with significant enrichment in low-CpG density regions, and are associated with brain-specific genes related to neuronal plasticity. Our study implicates modification of the neuronal DNA methylome as a previously under-appreciated mechanism for activity-dependent epigenetic regulation in the adult nervous system. I will present our latest progress on molecular mechanisms regulating DNA methylation dynamics in the adult brain, genome-wide analysis of DNA modifications, and implication of active DNA demethylation in mental disorders.

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Haruhiko Siomi, Ph.D

(Tokyo ,Japan)

Haruhiko Siomi is a Professor in the Department of Molecular Biology at Keio University School of Medicine ( He obtained his Diploma degree (1982) and M.S. degree (1984) in Agricultural Chemistry from Gifu University, where he studied stereoselective glycoside synthesis of biologically unique sugars, and his Ph. D. (1988) in virology from Kyoto University, where he studied gene expression of human T-cell leukemia virus type 1 (HTLV1). He was then an HHMI associate with Gideon Dreyfuss at the University of Pennsylvania School of Medicine, where he studied RNA-binding proteins, such as hnRNP proteins and FMR1. He joined the University of Tokushima faculty in 1999 where he was full Professor. In 2008, he moved to his current position at Keio University. His research focuses on many aspects of RNA silencing including siRNA biogenesis, miRNA biogenesis, piRNA biogenesis, transposon silencing, heterochromatin formation, Argonaute proteins and their roles in transcriptional and post-transcriptional silencing. He has been a member of the RNA Society and chaired sessions at annual RNA meetings and served as co-organizer of the RNA 2011 meeting in Kyoto. Since 2008, he has served as co-chair of the Tokyo RNA Club. He is currently an Associate Editor at Genes to Cells, and serves on the Editorial Boards of Nucleic Acid Research and EMBO reports.

Biogenesis of PIWI-interacting RNAs and transposon slicing in Drosophila
Haruhiko Siomi
Keio University School of Medicine, Tokyo, Japan
RNA silencing pathways are evolutionarily conserved cellular processes that participate in essential cellular functions ranging from the regulation of mRNA turnover to the suppression of the activity of potentially deleterious transposable elements (TEs). In Drosophila, the Argoanute family consists of five members. Of those, the PIWI subfamily proteins specifically associate with Piwi-interacting RNAs (piRNAs) and function in genome surveillance by silencing mobile elements in gonads. Our current focus is to understand the mechanisms of how piRNAs are produced and direct TE silencing in Drosophila. To elucidate the molecular mechanism of the primary piRNA pathway, we have used the ovarian somatic cell (OSC) line. We have found that piRNAs are processed from long single-stranded RNAs by a Dicer-independent pathway and are loaded onto Piwi in the cytoplasmic Yb body in OSC cells. The Piwi–piRNA complexes are then transported into the nucleus to exert TE silencing. The details will be discussed at the meeting.

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Session 2,
Epigenomic Perspectives of the complex biological systems (Afternoon, 20 April)

Hendrik G. Stunnenberg, Ph.D

(Nijmegen, The Netherlands)

Hendrik G. Stunnenberg is full professor and head of the Department of Molecular Biology, Faculty of Science and Medicine, Radboud University Nijmegen, The Netherlands and member of EMBO. He is organizer of the EMBL bi-annual meeting on transcription and chromatin. He is the coordinator of the EU-FP7 High Impact Project BLUEPRINT ( .He is member of the International Scientific Steering Committee of the IHEC ( He is partner in the International Cancer Genome Consortium (ICGC) and member of the Technical Working Group for Epigenetics. Research at his department focuses on the regulation of gene transcription and chromatin in normal and deregulated cells.

The Transcriptional and Epigenome Foundations of Ground State Pluripotency
Hendrik Marks1, Tüzer Kalkan2, Roberta Menafra1, A. Francis Stewart3, Austin Smith2, Hendrik G. Stunnenberg1,
1Molecular Biology, NCMLS, Radboud University, Nijmegen, The Netherlands
2Wellcome Trust Centre for Stem Cell Research, Department of Biochemistry, University of Cambridge, United Kingdom
3Genomics, BioInnovationsZentrum, Technical University Dresden, Germany
Mouse embryonic stem (ES) cells are characterized by the plasticity to generate all somatic and germline lineages in vitro and in chimeric embryos. The nature of the transcriptional and epigenetic machinery that maintains this potential throughout massive in vitro expansion has been the subject of intense investigation. ES cells have been described as transcriptionally hyperactive. Promiscuous transcription has been suggested to constitute a platform for lineage specification. Attention has also focused on the co-localization at many promoters of histone 3 lysine 4 trimethylation (H3K4me3), associated with transcriptional activation, and histone 3 lysine 27 trimethylation (H3K27me3), linked with repression. These bivalent domains are posited to be poised for either up- or down-regulation, providing an epigenetic blueprint for lineage determination.
However, mES cells grown in serum exhibit greater heterogeneity in morphology and expression of pluripotency factors than ES cells cultured in defined medium with inhibitors of two protein kinases (Mek and GSK3), a condition known as ‘2i’ that is postulated to establish a naïve ground state. We show that the transcriptome and epigenome make-up of serum- and 2i-grown ES cells are distinct. 2i-treated cells exhibit lower expression of lineage-affiliated genes but also reduced prevalence at promoters of the repressive histone modification H3K27me3 and fewer bivalent domains, which are thought to mark genes poised for either up- or down-regulation. Nonetheless, 2i-grown ES cells can differentiate rapidly. Precocious transcription of developmental genes in 2i is restrained by RNA polymerase II promoter-proximal pausing. Our findings suggest transcriptional potentiation and a permissive chromatin context characterize the ground state and that exit from it may not require a metastable intermediate.

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Tapas K Kundu, Ph.D

Bangalore, India

Professor Tapas K. Kundu completed his Ph.D. working with Prof. M.R.S. Rao, in the Indian Institute of Science, Bangalore, India. Later on, he was a postdoctoral researcher with Prof. Akira Ishihama at the National Institute of Genetics, Japan, and continued his post doctoral work with Prof. Robert G Roeder at the Rockefeller University, New York, where he contributed significantly to the field of chromatin mediated transcription regulation. In 1999, he joined the Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore. Prof. Kundu has made outstanding contribution in the area of regulation of human gene expression (transcription) and its link to disease and therapeutics. He is not only elucidating the mechanisms of transcription regulation through the epigenetic modifications in humans, but also targeting them to design new generation cancer diagnostics, as well as therapeutics for Cancer, AIDS and Diabetes. In brief, he has discovered transcriptional coactivator, PC4 as a novel non-histone component of chromatin and activator of p53 function. The Nucleolar protein, NPM1 was shown to have RNA polymerase II driven transcriptional coactivation activity which is acetylation and chromatin dependent. Presently, they have linked this function to cancer manifestation. They have elegantly, discovered several small molecule modulators of chromatin modifying enzymes which could serve as excellent molecular probes to understand the functions of these enzymes in vivo and also be useful to design new generation therapeutics. Over the years, he has published several research papers in many international journals such as Journal of Biological Chemistry, Molecular and Cellular Biology, Chemistry and Biology, Journal of Medicinal Chemistry, Molecular Cell, Nano letters, etc. Recently, Professor Kundu edited a book, entitled “Chromatin and Disease”, published by Springer press. Several patents on small molecule modulators of chromatin modifying enzymes from the laboratory have been granted and or under process. This also includes several academically important research reagents with potential commercial values, some of which have already been commercialized by renowned companies. He was awarded the prestigious, Shanti Swarup Bhatnagar Prize in the year 2005 and he is also a Fellow of The National Academy of Sciences, India (FNASc), 2005, Fellow of Indian Academy of Sciences (FASc), 2008 and Fellow of Indian National Science Academy (FNA), 2009. Recently, he has received one of the most prestigious, Sir J C Bose National Fellowship from Department of Science and Technology, Govt. of India. He is an editorial board member of the Journal of Biological Chemistry.

Histone arginine methylation in cancer and differentiation
Tapas K. Kundu
Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India
Epigenetic modifications fine tune the regulation of gene expression and thereby play pivotal roles in the process of differentiation and development. The altered function of any epigenetic modification also seriously affects the physiological homeostasis and thus becomes the fundamental cause of different pathophysiological conditions such as cancer. We have found that histones and histone chaperone NPM1 are significantly hyperacetylated in oral cancer due to the hyper-autoacetylation of p300. Acetylation and arginine methylation cooperatively function to activate transcription. The histone modification language for the transcriptional activation is possibly highly complex and epigenetic signal dependent. However, specific acetylation and asymmetric arginine methylation could be common codes for several types of transcriptional activation. Our initial observations suggest that indeed specific arginine residue is hypermethylated in the malignant sample, suggesting that the small molecule modulators of arginine methylation and histone acetylation may serve as potential therapeutic agents for the oral cancer. We have discovered a highly specific small molecule modulator of H3R17 methylation. This molecule presently has also been used to understand the role of H3R17 methylation in the process of differentiation using human embryonic stem cells as well as Zebra fish model.

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Bing Ren,Ph.D

(San Diego ,USA)

Dr. Ren is currently Member of the Ludwig Institute for Cancer Research (LICR) and Professor of Cellular and Molecular Medicine at the University of California, San Diego School of Medicine. He currently leads the San Diego Epigenome Center, one of four NIH-sponsored Reference Epigenome Mapping Centers. He obtained his Ph.D. from Harvard University in 1998, where he studied mechanisms of transcriptional repression under the guidance of Dr. Tom Maniatis. From 1998 to 2001, he continued to research mechanisms of gene regulation and genomics as a postdoctoral fellow in Dr. Richard Young’s laboratory at Whitehead Institute. During this period he pioneered the ChIP-chip analysis method. When Dr. Ren began his faculty appointment, he combined the ChIP-chip with genome tiling arrays to investigate the mechanisms of gene regulation in human cells. His group is among the first to demonstrate the use of high-resolution genome tiling arrays for mapping cis-regulatory elements. His recent works include generation of genome-wide maps of promoters, enhancers and potential insulators in human cells, and the discovery of distinct chromatin modification signatures for promoters and enhancers.

Analyses of Parent-of-origin and Sequence Dependent DNA Methylation in the Mouse Genome
Differential methylation of the two parental genomes in placental mammals is essential for genomic imprinting and embryogenesis. To systematically study this epigenetic process, we have generated a base-resolution, allele-specific DNA methylation (ASM) map in the mouse genome. We found parent-of-origin dependent (imprinted) ASM at 1,952 CG dinucleotide sequences (CGs), which form 55 discrete clusters including virtually all known germline differentially methylated regions (DMRs) and 23 previously unknown DMRs with some occurring at microRNA genes. By contrast, we identified sequence dependent ASM at 131,765 CGs. Interestingly, methylation at these sites exhibits a strong dependence on the immediate adjacent bases, allowing us to define a conserved sequence preference for the mammalian DNA methylation machinery. Finally, we report a surprising presence of non-CG methylation in the adult mouse brain, with some showing evidence of imprinting. This study provides a resource for understanding mechanisms of imprinting and allele-specific gene expression in mammalian cells.

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Young-Joon Kim, Ph.D

(Seoul ,Korea)

Young-Joon Kim is Underwood Distinguished Professor of Biochemistry department at Yonsei University and Director of the Yonsei Genome Institute.  His primary research interests are in the regulatory mechanism of mouse innate immune system and epigenetic regulation of disease-associated gene expressions. He received his BS degree from Seoul National University, and his Ph.D. degree from Stanford University in 1992.  He completed postdoctoral studies at the Roger Kornberg’s laboratory, where he discovered Mediator complex, the primary coactivator complex required for RNA polymerase II-mediated transcription. He joined the faculty of Samsung Biomedical Research Institute in 1994, and moved to the Yonsei University in 2001. He has served on the Review committee  (2003-2008) and Council of Scientists (2008-2012) of Human Frontier Science Foundation, and AACR international human epigenome taskforce team (2004-2009). He served as the Chair of the Academic Program Committee in the Federation of Asian and Oceanian Biochemistry and Molecular Biology Conference  (2007), and International Cell Biology Congress (2008). Dr. Kim has been the vice president of Korean Genomics Organization (2009-present). He has been serving as a vice chair of the Council of Scientist of Human Frontier Science Program (2010-present).

Distinctive role of DNA methylation in the epigenetic regulation of disease associated genes.
Sunmin Lee, Minkyun Bae, and Young-Joon Kim
Epigenetic alteration of gene expression is a common event in human cancer. DNA methylation is a well-known epigenetic process, but verifying the exact nature of epigenetic changes associated with cancer remains difficult. Here, we profiled the methylome of various human diseases using a methylated DNA enrichment technique (methylated CpG island recovery assay) in combination with a genome analyzer and a new normalization algorithm and found disease-specific aberrant mathylation patterns. Using this approach, we were able to gain a comprehensive view of promoters with various CpG densities, including CpG Islands (CGIs), transcript bodies, and various repeat classes. We found that gastric cancer was associated with hypermethylation of 5’ CGIs and the 5’-end of coding exons as well as hypomethylation of repeat elements, such as short interspersed nuclear elements and the composite element SVA. On the other hand, cystic kidney samples showed strong hypermethylation pattern at the genebody areas, which correlated with down regulation of the genes. These findings will provide valuable data for future analysis of disease methylation patterns, useful markers for the diagnosis of cancer and differentiation defects, as well as a new analysis method for clinical epigenomics investigations.

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Susan Clark,Ph.D

(Sydney, Australia)

Professor Susan Clark graduated in 1982 with a phD in Biochemistry at the University of Adelaide, Australia and then spent ten years in the Biotechnology Industry before returning to basic research in gene regulation in 1992 at Royal Prince Alfred Hospital, Sydney. In 2004, she was appointed Principal Research Fellow (NHMRC) and Professor and Head of the Epigenetics Group at the Garvan Institute of Medical Research in Sydney, Australia. Her studies over the last eighteen years have addressed profound questions about the importance of epigenetics in early development and in disease, especially in cancer. Susan has made extensive ground-breaking discoveries relating to DNA methylation patterns in normal and cancer genomes, that have led to new tests for early cancer detection. The techniques she pioneered in the early 1990s, including bisulphite sequencing, have revolutionised and now underpin a new era in epigenetics research. She is founder and president of the Australian Epigenetic Alliance (AEpiA) and Editorial Board Member for Epigenomics. She has a number of awards including “Biochemisch Analytik Preis 2004” for outstanding contribution for Methylation analysis.

Polycomb H3K27me3 and DNA methylation repressive marks are redistributed in cancer in a genomic region dependant manner
Susan J. Clark, Epigenetics Group, Cancer Program, Garvan Institute of Medical Research, Sydney 2010, New South Wales, Australia
The complex relationship between DNA methylation, chromatin modification and underlying DNA sequence is often difficult to unravel with existing technologies. Using a novel technique based on high throughput sequencing of bisulphite-treated chromatin immunoprecipitated DNA (BisChiP-seq), we can directly interrogate genetic and epigenetic processes that occur in normal and diseased cells. Unlike most previous reports based on correlative techniques, we found using direct bisulphite sequencing of polycomb H3K27me3-enriched DNA from normal and prostate cancer cells that DNA methylation and H3K27me3-marked histones are not always mutually exclusive, but can co-occur in a genomic region dependant manner. Notably, in cancer the co-dependency of marks is largely redistributed with an increase of the dual repressive marks at CpG islands and transcription start sites of silent genes. In contrast, there is a loss of DNA methylation in intergenic H3K27me3-marked regions. Allele-specific methylation status derived from the BisChIP-seq data clearly showed that both methylated and unmethylated alleles can simultaneously be associated with H3K27me3 histones, highlighting that DNA methylation status in these regions is not dependent on polycomb chromatin status. BisChIP-seq is a novel approach that can be widely applied to directly interrogate the genomic relationship between allele-specific DNA methylation, histone modification or other important epigenetic regulators.

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Daeyoup Lee, Ph.D

(Daejeon, Korea)

Daeyoup Lee, PhD, Assistant Professor, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Korea, South. Dr. Lee graduated from Department of Biological Sciences, KAIST, and began his research career investigating the regulatory mechanism of DNA replication by SWI/SNF ATP-dependent chromatin remodeling complex using human papillomavirus as a model system. After he received his Ph.D. from KAIST in 1999, he moved to USA to study chromatin biology. After he finished his postdoc in Stowers Institute (advisor: Dr. Jerry L. Workman), he was appointed as an Assistant Professor at KAIST, in 2006. Dr. Lee investigates the epigenetic mechanisms involved in transcription elongation using yeast and mammalian systems. His current research also focuses on the link between epigenetic control mechanisms and transcription elongation. Dr. Lee is a co-organizer of Epigenomics/chromatin biology section of Korean Society of molecular biology and Cell biology (2010-2011).

Genome-wide profile reveals an important role for H2B mono-ubiquitylation and hDot1L in transcription elongation of human cells
Daeyoup Lee, PhD.
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
H2B mono-ubiquitylation is required for multiple methylations of both H3K4 and H3K79 and has been implicated in gene expression from yeast to human. However, molecular crosstalk between H2BUb1 and other modifications, especially H3K4 and H3K79 methylations, remains unclear in vertebrates. To understand the functional role of H2BUb1, genome-wide histone modification patterns were measured in human cells. This study proposes dual roles of H2BUb1 that are both H3 methylation dependent and independent. First, H2BUb1 is a 5’-enriched active transcription mark and is co-occupied with H3K79 methylations in actively transcribed regions. Importantly, this study found a unique role of H2BUb1 in chromatin architecture independent of histone H3 methylations. H2BUb1 is well positioned in exon-intron boundaries of highly expressed exons and is specifically enriched in 5’-biased exons. Furthermore, H2BUb1 demonstrates increased occupancy in skipped exons compared to flanking exons for the human and mouse genome. Our findings suggest that a potentiating mechanism links H2BUb1 to both H3K79 methylations in actively transcribed regions and the exon-intron structure of highly expressed exons through the regulation of nucleosome dynamics during transcription elongation.

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Shyam Prabhakar, Ph.D


Shyam Prabhakar obtained a B.Tech in Electronics and Communications Engineering at the Indian Institute of Technology, Madras and a PhD in Applied Physics at Stanford University. His PhD thesis received the American Physical Society’s award for “Outstanding Doctoral Thesis Research in Beam Physics.” He underwent postdoctoral training in genomics under Eddy Rubin at the Lawrence Berkeley National Laboratory, where he devised and applied comparative genomic methods for studying transcriptional enhancers active in the developing mammalian embryo, including enhancers that potentially contribute to uniquely human traits such as the opposable thumb. Following this, he took up an independent position at the Genome Institute of Singapore, where he is now a Group Leader. His group uses both computational and experimental techniques to investigate the molecular basis of human transcriptional regulation in the contexts of development, disease and human population variation. Many projects in the group involve the use of chromatin profiling to obtain insights into enhancer and promoter functional states genome-wide.

Uniform, optimal framework for integrative analysis of chromatin profiles
Vibhor Kumar1, Masafumi Muratani2, Nirmala Arul Rayan1, Petra Kraus2, Thomas Lufkin2, Huck Hui Ng2, Shyam Prabhakar1
1. Computational and Systems Biology
2. Stem Cell and Developmental Biology, Genome Institute of Singapore
High-throughput DNA sequencing is used in diverse functional assays, and an even more diverse set of computational tools has been developed to analyze the resulting data. We propose that this algorithmic diversity obscures the underlying similarity of many of the data analysis tasks, and introduce a more unified approach. The approach is based on collapsing multiple analysis problems into two coherent categories, signal detection and signal estimation, and implementing linear-optimal solutions that are widely used in the field of signal processing. Importantly, our algorithms for detection (DFilter) and estimation (EFilter) extend naturally to integration of multiple datasets.
In benchmarking tests, DFilter consistently outperformed assay-specific algorithms at identifying promoters from histone ChIP-seq, binding sites from transcription factor (TF) ChIP-seq and open chromatin regions from DNase-seq and FAIRE-seq data. We used the method to compare the latter two assay types, and uncovered significant differences in promoter-vs-enhancer specificity and signal-to-noise ratio. EFilter similarly outperformed an existing method at predicting mRNA levels from histone ChIP-seq data, and suffered negligible reductions in accuracy when training and test data were derived from different cell types. EFilter achieved high accuracy when trained on as few as 2-3 histone ChIP-seq profiles (Spearman correlation: 0.81-0.92), suggesting that chromatin states are highly predictive of mRNA levels. Conversion of histone modification profiles into gene expression estimates creates novel applications for a large set of bioinformatic techniques traditionally used in microarray data analysis.
In order to gain insights into developmental gene regulation using these methods, we performed H3K4me3 and H3K36me3 ChIP-seq on mouse forebrain tissue at embryonic day 11.5 (e11.5). We used DFilter to identify active promoters, and EFilter to predict expressed gene bodies, resulting in the detection of hundreds of unannotated transcripts, including two novel genes that we subsequently validated by RT-PCR in mouse embryonic forebrain. Promoter sequence analysis highlighted SOX2, NRSF, E2F1 and TEF motifs as the top four correlates of forebrain-specific (predicted) expression, and revealed a network of NRSF target genes with synaptic function that are presumably de-repressed when NRSF is downregulated from e9.5 to e11.5, as neuronal precursors switch from proliferation to differentiation.

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Sheng Zhong, Ph.D

(Illinois, USA)

Dr. Zhong is an Associate Professor with tenure at University of Illinois Urbana-Champaign. After receiving his PhD of biostatistics at Harvard University, he became a visiting scholar of systems biology at Stanford University. He joined University of Illinois as an assistant professor in 2005, and became an associate professor in 2011. His lab integrates experimental and computational advances to study epigenetic functions in stem cells and cancer. He was elected as a Faculty Fellow of National Center for Supercomputing Applications in 2007 and as an Associate for Center for Advanced Study in 2012. He received Xerox Award for Research in 2008, NSF CAREER Award in 2009, NIH Director's New Innovator Award in 2010. Nature featured his research as a Research Highlight in 2010.

Comparative epigenomics
Sheng Zhong, Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA
Despite the explosive growth of genomic data, functional annotation of the regulatory sequences remains difficult. Here we introduce ‘comparative epigenomics’ – interspecies comparison of epigenomes – as a novel approach for annotation of the regulatory genome. We measured in human, mouse, and pig pluripotent stem cells the genomic distributions of nine epigenomic marks, four transcription factors, and transcribed RNAs. We made the unexpected observation that epigenomic conservation was strong in both fast-evolving and slowly evolving DNA sequences, but not in neutrally evolving sequences. In contrast, evolutionary changes of the epigenome and the transcriptome exhibited a linear correlation. We suggest that the conserved co-localization of different epigenomic marks can be used to discover regulatory sequences. Indeed, seven pairs of epigenomic marks thus identified exhibited regulatory functions during differentiation of embryonic stem cells into mesendoderm cells. Thus, comparative epigenomics reveals regulatory features of the genome that cannot be discerned from sequence comparisons alone.

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Session 3,
Epigenetics in Cancer (Morning, 21 April)

Qian Tao, Ph.D

(Hong Kong)

Dr. Tao obtained his PhD in Molecular Pathology from the University of Hong Kong and did his postdoct training in the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine from 1995 to 1998. He was appointed as an Assistant Professor in Johns Hopkins Medicine in 1999, and promoted to Associate Professor in 2004, and Professor in 2008 in the Chinese University of Hong Kong. He leads the Cancer Epigenetics Laboratory in the State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Faculty of Medicine, the Chinese University of Hong Kong. Dr. Tao’s major research interest is cancer epigenetic(-omic)s - the identification of novel tumor suppressor genes silenced by promoter CpG methylation in tumors through integrative epigenomics, and the further functional/mechanistic characterization of these genes. He has published over 100 papers in international journals including Lancet, Blood, JCO, HMG, Cancer Res, Oncogene and PNAS. He serves as an Academic Editor for PLoS ONE and external reviewer for 48 scientific journals. He is currently a vice-President of the international Epigenetics Society.

Epigenetic disruption of cell signaling regulation in human cancers.
Cancer Epigenetics Laboratory, Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong.
Tumorigenesis involves multiple alterations of critical cancer genes including the epigenetic disruption of tumor suppressor genes (TSGs) through promoter CpG methylation. Epigenetic abnormalities also provide us with useful biomarkers for novel TSG identification and early cancer diagnosis. Through integrative cancer epigenomics, we have identified a series of methylated novel genes in tumors, including multiple regulator genes of cell signaling pathways, such as PCDH10, RASAL1, UCHL1, ZNF382 and CHD5. Further functional and mechanistic studies demonstrated that the epigenetic silencing of these TSGs leads to the disrupting of cell signaling pathways such as WNT/b-catenin, Ras/Rho, p53 and nuclear signaling, which further causes de-regulation of cell cycle, apoptosis and promotes tumor cell metastasis/invasion as well as stemness. Moreover, the tumor-specific methylation of these genes could serve as non-invasive epigenetic biomarkers for early tumor diagnosis and prognosis prediction.

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Toshikazu Ushijima, Ph.D

(Tokyo, Japan)

Dr. Toshikazu Ushijima, Senior Deputy Director and Chief of Division of Epigenomics, National Cancer Center Research Institute (NCCRI), Tokyo, graduated from University of Tokyo School of Medicine in 1986.  He started his research career at NCCRI in 1989, and was promoted to Chief of Carcinogenesis Division (now Division of Epigenomics) in 1999.  He developed one of the first genome-wide screening techniques for changes in DNA methylation, methylation-sensitive representational difference analysis (MS-RDA), in 1997.  Using MS-RDA, he identified a novel tumor-suppressor gene in gastric cancers, and isolated a very powerful prognostic marker in neuroblastomas.  His major contribution to cancer epigenetics is establishment of the concept "epigenetic field for cancerization".  Environmental factors, such as Helicobacter pylori infection and cigarette smoking, can induce aberrant DNA methylation of multiple specific genes in normal-appearing tissues, and accumulation of such aberrant DNA methylation produces an epigenetic field for cancer development.  He is now investigating the mechanisms how aberrant DNA methylation is induced.  He is serving as an editor for Cancer Research (Senior Editor), Cancer Science (Associate Editor), Cancer Letters (Editor), and Gastric Cancer (Associate Editor), and as a board member for Cancer Prevention Research, Epigenomics, Clinical Epigenetics, and the Journal of Molecular Medicine.

Induction Mechanisms of Aberrant DNA Methylation
Aberrant DNA methylation can lead to various acquired disorders, including cancer, and its inducer and induction mechanisms are of great importance for public health. We previously demonstrated that, in human gastric mucosae, Helicobacter pylori (H. pylori) infection was associated with high methylation levels [Maekita, Clin Cancer Res, 2006], and that eradication of H. pylori leads to decreases of methylation levels at various degrees [Nakajima, J Gastroenterol, 45:37, 2010]. Using Mongolian gerbils, it was shown that H. pylori infection was causally involved in methylation induction, and that inflammation induced by the infection, not H pylori itself, was essential for methylation induction [Niwa, Cancer Res, 70:1430, 2010]. In contrast, inflammation induced by high concentrations of NaCl or ethanol did not induce aberrant DNA methylation even if the inflammation persisted for a prolonged period [Hur, Carcinogenesis, 2011]. Further, using mouse colitis model, it was shown that methylation could be induced even in SCID mice that lack T- and B-lymphocytes, suggesting a critical role of monocytes [Katsurano, Oncogene, 31:342, 2012]. No changes in expression levels of Dnmt1, Dnmt3a, or Dnmt3b were observed in tissues with inflammation. These showed that specific types of inflammation are important for induction of aberrant DNA methylation, and suggested that cytokines and signals from monocytes might lead to imbalance between DNA methylation machinery and protection systems in epithelial cells. Such cytokines and signals are considered to provide good targets for disease prevention.

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Yutaka Kondo, M.D., Ph.D.


Yutaka Kondo is a Section Head in Division of Molecular Oncology, Aichi Cancer Center Research Institute. He received his M.D. from Nagoya City University Medical School in 1990 and his Ph.D. from Nagoya City University Graduate School of Medical Science in 2000. After his postdoctoral research with Professor Jean-Pierre Issa in the Department of Leukemia at the University of Texas, MD Anderson Cancer center, he joined the faculty of MD Anderson Cancer center in 2004. In 2005, he joined the faculty of Aichi Cancer Center Research Institute and now is the Section Head of Division of Molecular Oncology. His work is focused on the regulation of gene expression by histone modifications and DNA methylation in human cancers, and the clinical implications of these aberrant changes. His works accomplished to date highlight the importance of histone modifications in cancers, their relationship with aberrant DNA methylation and gene silencing, and the potential in gene discovery. Now his interest is in epigenetic plasticity in cancer stem cells.

Polycomb repressive complex 2-mediated epigenetic plasticity contributing to establishment of tissue heterogeneity in glioblastoma
Division of Molecular Oncology, Aichi Cancer Center Research Institute
Cancers are mostly comprised of heterogeneous cell populations. Such multiple distinct subpopulations of cancer cells within tumors may derive from a limited source of cancer cells that have plasticity and respond to signals they receive from their microenvironment. Recent studies have revealed that glioblastoma contain a minor population of tumor-initiating cells, called glioma stem-like cells (GSCs).
Alongside known genetic changes, aberrant epigenetic alterations have emerged as common hallmarks of many cancers. Epigenetic silencing in cancer cells is mediated by at least two mechanisms, polycomb repressive complex 2 (PRC2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methylation-mediated gene silencing, the latter of which is closely associated with H3K9me2.
To uncover the underlying mechanisms of heterogeneity, we established GSCs from the primary glioblastomas. Cells expressing GFP derived by Nestin-promoter were further isolated for the precise studies of GSCs, which shared the characters with neural stem cells. We examined GSCs and found that biological interconversion between GSCs and differentiated non-GSCs is functionally plastic and accompanied by gain or loss of PRC2-mediated H3K27me3 on pluripotency or development associated genes (e.g. Nanog, Wnt1, BMP5) together with alterations in the subcellular localization of EZH2, a catalytic component of PRC2. In addition, PRC2-mediated epigenetic regulatory pathways of microRNAs (e.g. miR-1275) were closely associated with oligodendroglial differentiation, which may contribute to the formation of heterogeneity in glioblastomas. Compellingly, the subcellular localization of EZH2 has been shown to be associated with tumor cell differentiation in glioblastoma specimens. Inhibition of EZH2 disrupted the morphological interconversion and impaired GSC integration into the brain tissue, resulting in improved survival of GSC-bearing mice. Our data suggest that epigenetic regulation by PRC2 is a key mediator of tumor cell plasticity. Targeting this plasticity through the underlying molecular mechanisms involved in tumor heterogeneity may be a novel strategy in glioblastoma treatment.

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Bin Tean Teh, MD, Ph.D


Dr. Bin Tean Teh  obtained his medical degree (1992) from the University of Queensland, Australia and his Ph.D. (1997) from the Karolinska Institute, Sweden.  Following postdoctoral work in multiple endocrine neoplasia 1 at Karolinska Institute, Dr Teh joined the Van Andel Research Institute (VARI, USA) as a Senior Scientific Investigator in the Laboratory of Cancer Genetics since January 2000. He is currently a Professor at the Duke-NUS Graduate Medical School, Singapore and serves as the Group Director for Translational Research at SingHealth. He also holds Adjunct Professorships Universities/Institutes in Sweden, USA, and China.  He also co-directs the Kidney Cancer Research Program at the Van Andel Research Institute in the USA.  Additionally, Dr. Teh has published extensively over 270 publications in high impact scientific journals and also sits on various Editorial Boards such as Lancet Oncology, Cancer Research, International Journal of Oncology, the Journal of Endocrine Genetics, the Journal of Clinical Endocrinology and Metabolism, Clinical Genitourinary Cancer, and the American Journal of Translational Research.

Chromatin Remodelers in Cancer
In the last two years, by using high-throughput Next-Generation Sequencing (NGS), we and others have identified frequent mutations in histone modifiers and chromatin remodellers in different cancer types. For example, in clear cell renal cell carcinoma, the most common type of kidney cancer,a gene called PBRM1, which encodes a member of the SWI-SNF complex, was found to be mutated in up to 40 percent of this cancer type. In gastric cancer, ARID1A, the counterpart of PBRM1 in the SWI-SNF complex, was found to be mutated in a subset of gastric cancer. Preliminary cellular studies involving these two genes in these two cancer types demonstrated their tumor suppressive roles. Additional gene expression profiling points to involvement of several known cancer-related biological pathways but their underlying mechanisms of acation require further invstigations. Besides these two genes, frequent mutations of other chromatin modifiers have also been identified including UTX in multiple cancers, MLL family in pancreticobiliary cancer, and many more. The lecture will discuss the direction of future studies in this field and their clinical implications.

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Jingde Zhu, Ph.D,

(Shanghai, China)

Jingde Zhu, is the leader of Cancer Epigenetics Program, since 2001. He obtained Ph.D (1985) in Beatson Institute for Cancer Research, Glasgow, UK. Then worked as a senior scientist or PI in Shanghai Institute of Cell Biology, three academic institutions and one biotech firm in UK between 1985-2001. His research focuses at the epigenetic (-omic) perspectives of cancer biology, with a great emphasis on the translational phase effort. His research are supported by the funds from the European 6th frame as well as from both local and central governments of China. Jingde Zhu is the inventor for both approved and filed patents in China (six) and in US(three).

DNA methylation cancer diagnostics: promises and challenges
Shanghai Cancer Institute/Renji Hospital,
Shanghai Jiaotong University, Shanghai 200032, China
DNA methylation is the best characterized component of the epigenetic interface, mediating mitotic and meiotic transmission of the transcription memory and therefore determining cell fate and phenotype of high eukaryotes. Aberrant DNA methylation is a hallmark of cancer, and other major diseases. In addition to the mechanistic insights, the robustness of the integrative approach to the DNA methylation cancer biomarkers for cancer early detection will be described. The a novel diagnostics (a multiplex qPCR kit/ DNA methylation profiling of 5 targets in urine sediment) for early detection, quality control of surgery and monitoring the recurrence of bladder cancer will be presented as a paradigm.

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Yi-Ching Wang, Ph.D


Yi-Ching Wang, PhD, is currently a Distinguished Professor of Department of Pharmacology and Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Prof. Wang received her Ph.D. from Genetic Program of Michigan State University in 1993. She studies the molecular mechanisms involved in lung tumorigenesis. Many evidences show that there are unique genetic and epigenetic alterations in Taiwanese lung cancer compared to that in other countries. Therefore, Prof. Wang investigates the etiological association of alterations in several tumor suppressor genes, oncogenes, and DNA repair genes with lung tumorigenesis. The alteration analyses include the following aspects: gene mutation and polymorphism, gene loss, hypermethylation of promoter, chromatin structure alteration of gene locus, mRNA alteration, and altered protein expression. More recently, Prof. Wang has continued to do research on cancer genomics and epigenomics such as genome-scanning approaches of DNA methylation and chromatin alteration profiles for identification of new genes critical to lung tumorigenesis. In addition, several potential epi-drugs are developing in her laboratory. Prof. Wang has published more than 50 SCI papers on lung cancer including prestigious journals such as J. Clin. Oncol., (SCI 18.970); J. Clin. Invest., (SCI 14.154); Cancer Res., (SCI 8.234); Oncogene (SCI 7.414); and Clin. Cancer Res., (SCI 7.338). Prof. Wang was one of the recipients for Excellent Research Award of Taiwan National Science Council.

Deregulation of transcriptional and post-translational controls of DNA methyltransferases in lung cancer
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
Overexpression of DNA 5’-cytosine-methyltransferases (DNMTs), which are enzymes that methylate the cytosine residue of CpGs, is involved in many cancers. However, mechanism of DNMT overexpression remains mostly unclear. Here, I will present our recent data on dysregulation of transcriptional and post-transcriptional controls of DNMT in cancer. For transcriptional control, wild-type p53 negatively regulated DNMT1 expression by forming a complex with Sp1 protein and chromatin modifiers on DNMT1 promoter. However, the stoichiometry between p53 and Sp1 determined whether Sp1 acts as a transcription activator or co-repressor. We discovered a new mechanism that high level of Sp1, via its C-terminal domain, induced interaction between p53 and MDM2 resulting in the degradation of p53 by MDM2 mediated-ubiquitination. Clinical data from 102 lung cancer patients indicated that overexpression of DNMT1 was associated with p53 mutation and high expression of Sp1 protein. Our cell and clinical data provided compelling evidence that deregulation of DNMT1 is associated with the gain of transcriptional activation of Sp1 and/or the loss of repression of p53. For post-transcriptional control, we revealed a mechanism from lung cancer cell, animal, and clinical studies whereby cigarette carcinogen NNK induced DNMT1 through inhibition of AKT/GSK3/TrCP degradation signaling and activation of AKT/hnRNP-U/TrCP nucleocytoplasmic shuttling leading to DNMT1 accumulation in nucleus and promoter hypermethylation of tumor suppressor genes. GSK3 phosphorylated DNMT1 to recruit TrCP resulting in DNMT1 degradation, while NNK activated AKT and inhibited GSK3b to attenuate DNMT1 degradation. NNK also induced TrCP translocation to cytoplasm via hnRNP-U shuttling protein resulting in DNMT1 nuclear accumulation. DNMT1 overexpression results in epigenetic alteration of multiple tumor suppressor genes and ultimately leads to lung tumorigenesis and poor prognosis. Metabolites are emerging as regulators of epigenetics

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Li-Jung Juan, Ph.D


Li-Jung Juan, PhD, a tenured Associate Research Fellow of the Genomics Research Center, Academia Sinica, Taipei, Taiwan, is interested in functions of chromatin modifiers in viral replication and cancer. She received BS degree from China Medical College in Taiwan in 1990 and Ph.D. degree from Penn State University in 1996 with Jerry Workman. She then received the 1st National Health Research Institute (NHRI) Distinguished Postdoctoral Fellowship Award for independent postdoctoral research at NHRI, Zhunan, Taiwan, and subsequently joined the faculty of the NHRI since 2000. In 2006, Dr. Juan moved to Genomics Research Center, Academia Sinica, Taipei, Taiwan. Dr. Juan has demonstrated that both the host histone acetyltransferase and methyltransferase activities can be suppressed by viral oncoproteins (EMBO 2004 and Oncogene 2011). She also showed that chromatin assembly factor 1 (CAF1) is required to activate HCMV viral gene transcription and replication (JBC 2009 and Cell Res 2011). A team with her as the co-corresponding author reported that the histone demethylase RBP2 interacts specifically with the DNA sequences CCGCCC via its ARID domain (Nat Struc Mol Biol 2008). Her group continued to show that the DNA binding function contributed to RBP2-mediated oncogenesis (to be submitted). In 2010, her group identified a novel pathway to control DNA methyltransferase 1 activity and recruitment to tumor suppressor genes in lung cancer formation by hNaa10p, an acetylase for both N-a-acetylation and internal lysine acetylation (JCI 2010). Dr. Juan received Academia Sinica Career Development Award and TienTe Lee Biomedical Young Investigator Award in 2009. She served on the International Scientific Committee (ISC) of the Asian Conference on Transcription (ACT) from 2002 to 2011, organized and co-chaired the Ninth ACT (ACT IX) at Zhunan, Taiwan, in 2005. She also organized the 1st Taipei Epigenetics and Chromatin Meeting in 2009.

DNA methylation and demethylation in cancer development
Li-Jung Juan
Genomics Research Center, Academia Sinica
128 Academia Rd., Sec. 2., Nankang, Taipei 115, Taiwan
Aberrant DNA methylation is a common feature of cancer. DNA methyltransferases (DNMTs) contribute to oncogenesis partly via methylating and inactivating tumor suppressor genes. One of the key questions is how DNMT activity and recruitment to target genes are regulated. We reported previously (JCI, 2010) that hNaa10p, an acetylase for both N--acetylation and internal lysine acetylation, contributes to lung tumorigenesis by targeting DNMT1 to specific tumor suppressor genes. The underlying mechanism may involve the recognition of unmethylated CpG by hNaa10p. Another burning issue is whether DNA demethylation counteracts the oncogenic effect mediated by DNMTs. TET1, a dioxygenase which converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine, is likely involved in the demethylation process. In the talk, first, the essential role of TET1 in cancer invasion will be demonstrated using cell-based assays, xenograft models and human clinical samples. Second, I will show that the MMP inhibitors TIMP family proteins are pivotal TET1 downstream effectors responsible for TET1-mediated invasion suppression. Third, the underlying mechanism by which TET1 activates TIMP gene expression will be discussed. Finally, I like to propose an upstream regulator contributing to TET1 loss during cancer formation. Together, our results establish TET1 as a novel invasion/metastasis suppressor partly via downregulating critical gene methylation (revision under consideration in Cancer Cell).

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Tohru Nakano, M.D., Ph.D.

(Osaka, Japan)

Toru Nakano is a Professor of the Department of Pathology, Osaka University Medical School, Osaka Japan. He received his M.D. from Osaka University Medical School in 1981. After working as a physician for three years, he worked from 1984 to 1988 at the Medical School where he was engaged in the transplantation experiments of mast cells and hematopoietic stem cells. From 1989, he joined to European Molecular Biology Laboratory (EMBL) as a visiting scientist and was involved in the viral leukemogenesis of chicken. As a staff scientist, he next went on to work, first as an assistant professor (1990) and then as a lecturer (1991) at the Faculty of Medicine, Kyoto University, on a project studying the molecular mechanisms of hematopoesis using his unique in vitro differentiation induction method from mouse ES cells. He took a professor position at the Research Institute for Microbial Diseases, Osaka University in 1995 and started his study of germ cell development. In 2004, he was appointed as a professor at the Graduate School of Frontier Biosciences and Medical School, Osaka University. His major interest is “How various kinds of cells are produced from single totipotent cells, zygotes?” Based on the interest, he has been studying epigenetic modification, especially DNA methylation, in spermatogenesis, early embryogenesis, and carcinogenesis. To be more precisely, his recent and major scientific themes are de novo DNA methylation of male germ cells by germ cell specific small RNA, pi-RNA (piwi interacting RNA), the regulation of DNA methylation in early embryogenesis, and DNA hypomethylation-induced transformation.

DNA Methylation in Cell Differentiation and Transformation
Toru Nakano1 and Toshinobu Nakamura2
1 Department of Pathology, Medical School and Faculty of Frontier Biosciences, Osaka University, Suita 565-0871, Osaka, Japan
2 Department of Animal Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Shiga, Japan
DNA methylation plays crucial roles in the development and many diseases including cancer. We have been analyzing the function of Stella, also known as PGC7 and Dppa3, a germ cell specific factor indispensable for preimplantation development. Recently we revealed that the function of Stella in early embryogenesis is brought about by the binding of Stella to chromatin via di-methylation of histone H3 lysine 9 (H3K9). In addition, we happened to find that PGC7 induced global DNA hypomethylation in the fibroblasts and subsequent transformation. Stella null condition induces a rapid decrease in 5-methylcytosine (5MeC) and a reciprocal increase in 5-hydroxymethylcytosine (5HmC) in the maternal genome of early embryos. Thus, Stella protects the DNA methylation by inhibiting the conversion of 5MeC to 5HmC in zygotes. However, it remained unclear what are the molecular mechanisms underlying the function of Stella. We carried out several lines of experiment such as ChIP assay, in vitro peptide binding assay, MNase assay, stepwise salt-extraction assay, and so on. Taken all the data together, we concluded that this reciprocal DNA modification is controlled by the binding of PGC7 to maternal chromatin containing H3K9me2 by presumably inhibiting the activity of the enzyme, Tet-3, which catalyzes from 5MeC to 5Hmc. In addition, the imprinted loci which are marked with H3K9me2 in mature sperm are also protected by the binding in early embryogenesis.
During the course of analyzing the molecular function of PGC7, we over-expressed the gene in NIH3T3 cells. Opposite to the function of PGC7 in zygotes, namely the protection of DNA methylation, DNA demethylation took place in a replication-dependent manner. Global DNA methylation analysis (MIAMI method; Microarray-based Integrated Analysis of Methylation by Isoschizomers) demonstrated that PG7 induced DNA demethylation throughout the genome in PGC7 expressing NIH3T3 cells.
In addition, PGC7-mediated DNA hypomethylation induced the transformation of the cells which showed loss of contact inhibition, anchorage-independent growth, and tumor formation in nude mice. Microarray gene expression analysis showed neither aberrant expression of oncogenes nor reduced expression of tumor suppressor genes in the transformed cells. These results suggest that global DNA hypomethylation per se is one of the pathogenic factors of cancer.

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Taiping Chen, Ph.D

(Houston, USA)

Taiping Chen, PhD, associate professor in the Department of Molecular Carcinogenesis at The University of Texas M.D. Anderson Cancer Center. Dr. Chen obtained his PhD in 2000 from McGill University (Montreal, Quebec, Canada), where he characterized the biochemical properties and biological functions of the GSG/STAR family of RNA-binding proteins. He then did his postdoctoral training at Massachusetts General Hospital, Harvard Medical School. Supported by fellowships from the Human Frontier Science Program and Canadian Institutes of Health Research, he conducted research on how DNA methylation is regulated during mouse development. In early 2004, Dr. Chen was recruited to Novartis Institutes for Biomedical Research (Cambridge, Massachusetts, USA) as a research investigator and laboratory head. The research in his group focused on the interplays and cooperation between the DNA methylation and histone methylation machineries in a variety of biological processes, including embryogenesis, genomic imprinting, and stem cell functions. In September 2011, Dr. Chen moved to M.D. Anderson Cancer Center (Smithville, Texas, USA). His group is continuing their work on the roles of epigenetic modifiers in mammalian development and diseases, particularly cancer. He recently received the CPRIT Rising Star Award (2011).

Epigenetic modifiers in mammalian development and disease
Taiping Chen, Ph.D.
Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, 1808 Park Road 1C, Smithville, Texas 78602, USA
Epigenetic modifications, including DNA methylation and histone modifications, play crucial roles in regulating chromatin structure and gene expression. Over the last two decades, great progress has been made in identifying the factors responsible for adding, erasing, and interpreting epigenetic marks. However, the biological functions of many epigenetic modifiers remain poorly understood. We use a variety of model systems, including genetically engineered mice, to investigate the roles of enzymes involved in DNA methylation and histone methylation in mammalian development, physiology, and human diseases. In this presentation, I will focus on non-histone substrates of "histone methylases" and the roles of protein methylation in cellular pathways.

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Kazuya Iwamoto, Ph.D


Kazuya Iwamoto is an Associate Professor at the Department of Molecular Psychiatry, the University of Tokyo. He graduated from Tokyo University of Agriculture and Technology, in 1996, and obtained his PhD in 2001 from the University of Tokyo. After that, he joined Kato Tadafumi’s lab at the RIKEN Brain Science Institute as a post doctor, and began the molecular biological studies about psychiatric diseases such as mood disorders and schizophrenia.  In 2010, he moved to the present address. His research focuses on revealing the genomic and epigenomic variations in the brains of patients with psychiatric diseases.

Epigenomics of brains of patients with bipolar disorder and schizophrenia
Kazuya Iwamoto1), Tadafumi Kato2)
1) Department of Molecular Psychiatry, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
2) Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako, Japan.
Despite the extensive efforts, genetic factors involved in psychiatric diseases such as bipolar disorder and schizophrenia remain largely unknown. Epigenetic factors, such as DNA methylation and histone modifications, play a key role in the long-lasting gene expression change. Although it would be reasonable to hypothesize that there may be epigenetic signature reflecting the pathophysiology of psychiatric diseases, identifying them is still challenging. One of the major problems is the cellular heterogeneity in the brain tissue, because it consists of many types of different cells such as neurons and glias. To address this issue, we have previously established a method for the separation of neuronal and non-neuronal nuclei from the fresh-frozen postmortem brain using NeuN-based cell sorting. By utilizing this separation method, we performed comprehensive DNA methylation analysis using brains of patients with schizophrenia (N = 35), bipolar disorder (N = 35) as well as controls (N = 35). Postmortem brains (prefrontal cortex, BA10) were obtained from the Stanley Medical Research Institute. To date, we identified the cell-type specific DNA methylation changes. Such DNA methylation changes may contribute to the pathophysiology of psychiatric diseases.

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Esteban Ballestar, Ph.D.

(Barcelona, Spain.)

Esteban Ballestar is leader of the Chromatin and Disease Laboratory at the Cancer Epigenetics and Biology Programme (PEBC) of the Bellvitge Biomedical Research Institute (IDIBELL) in Barcelona, Spain. Ballestar obtained his Ph.D. degree from the University of Valencia under the supervision of Luis Franco, specialising in chromatin and histone modifications (1997). He then worked as a Postdoctoral Fellow at the National Institutes of Health, (Bethesda, MD, USA) in the laboratory of Alan Wolffe where he investigated associations between elements of the chromatin machinery and methylated DNA. From 2001 to 2008, Esteban Ballestar has worked at the CNIO Cancer Epigenetics Laboratory, in association with Manel Esteller, where his principal area of research has been the study of the implication of chromatin factors in epigenetic alterations in human cancer. His current research is devoted to the establishment of different mechanisms of epigenetic deregulation in the context of the hematopoietic system in autoimmune diseases, hematological malignancies as well as in different differentiation models. Recent findings from his research group include the identification of a signature of DNA methylation alterations associated with systemic lupus erythematosus. Author of more than seventy peer-reviewed manuscripts in biomedical sciences, he is also a member of numerous international scientific societies and reviewer for many journals and national and international funding agencies.

Epigenetic Dysregulation in Immune System Models
Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain
Correct function of the immune system depends on multiple cell commitment and differentiation steps, and adequate control of a variety of activation events. Dysregulation of gene expression in immune cells plays a major role in the development of haematological malignancies, autoimmune diseases or immunodeficiencies. Interplay between transcription factor activity, epigenetic mechanisms and miRNA expression are key in the establishment of gene expression patterns and therefore determine the identity and function of relevant immune cell types. Genetic variability influences the integrity and function of these elements, although environmental factors can also modulate epigenetic mechanisms and ultimately participate in the development of immune-related diseases. Here, the contribution of epigenetic and miRNA control in different immune system models associated with both autoimmune diseases and haematological malignancies will be discussed. Specifically I will present both the participation of epigenetic mechanisms and miRNA dysregulation in three different models: i) monozygotic twins discordant for autoimmune diseases, ii) a differentiation model associated with the ectopic expression of a transcription factor in pre-B cells (modeling events that occur in leukemias), and iii) a model where resting B cells are infected by epstein-barr virus, an etiopathogenic factor in both haematological malignancies and autoimmune diseases. It is hoped that this presentation sheds light on how epigenomic analysis and high-throughput screening of miRNA expression can help to understand the molecular basis of these diseases and how this information can be used in the clinical setting.

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Deyu Fang, Ph.D
Title: Sirtuin 1 in immune regulation and autoimmunity

Deyu Fang, Ph.D., is an Associate Professor in the Department of Pathology at the Feinberg School of Medicine, Northwestern University.   He has been trained as a medical doctor from Weifang Medical College in China (1986-1991) and earned his PhD in biomedical research in Gunma University School of Medicine (1995-2000).   He then did his postdoctoral training in molecular immunology in La Jolla Institute for Allergy & Immunology (2000-2003) and biotechnology in University of Michigan (2003-2005).  In 2005, he was recruited as an Assistant Professor in the University Of Missouri School of Medicine and promoted to an Associate Professor in Northwestern University Feinberg School of Medicine in 2009. Since completion of his training, Dr. Fang has been engaged in basic and clinical research, in particular the post-translational protein modification including acetylation and ubiquitination in immune regulation and autoimmunity. His research has been continuously supported by the NIH and the Arthritis Foundation and he is selected as one of the ten NIH Director awardees of the “type 1 diabetes pathfinder” program in 2008.  In addition, he has received an Arthritis Foundation new investigator award and the 2008 Dorsett Spurgeon Distinguished Medical Research Award.  He has actively served on peer-review study sections for NIH, the Arthritis Foundation and the American Heart Association. 

Sirtuin 1 in immune regulation and autoimmunity
Heeyoung Yang, Zhenghong Lin, Kyeorda Kemp, Sinyi Kong and Deyu Fang
Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E Chicago Ave, Chicago, IL 60612, USA.
The NAD-dependent histone deacetylase sirtuin 1 (Sirt1) is implicated in a wide variety of physiological processes, ranging from tumorigenesis to mitochondrial biogenesis to neuronal development. Our laboratory has recently shown that Sirt1gene expression is induced by self-antigen and that the upregulated Sirt1 plays an essential role in maintaining peripheral T cell tolerance by inhibiting the transcription factors AP-1 and NF-B for IL-2 production (JCI, 2009) and deacetylating histone H3 lysine 56 to suppress the expression of Bcl2-associated factor (Bclaf1) in T cells (JBC, 2011). As a consequence, small molecule activators of Sirt1, such as resveratrol show great therapeutic potentials in autoimmune disease treatment (Diabetologia, 2011). We further demonstrated that IL-2 down-regulates Sirt1 gene transcription through PI3K-mediated sequestration of FoxO3a in tolerized T cells, proving a molecular explanation for IL-2-mediated breakdown of T cell anergy (PNAS, 2012). Utilizing a proteomic approach, we have identified a Sirt1-interacting protein complex including the ubiquitin-specific peptidase 22 (USP22). Our biochemical and genetic studies indicate that USP22 is a K63-specific deubiquitinase of Sirt1 to antagonize Sirt1 functions in immune regulation and cancer development (Molecular Cell, in press). More recently, we have shown that Sirt1plays a critical role in dendritic cell functions in regulating the regulatory T cell (Treg) and Th17 differentiation during inflammation (Manuscript under submission). Therefore, our studies indicate that Sirt1 is a critical regulator of both the innate and adaptive immune response in mice and its altered functions are likely involved in autoimmune diseases.

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Prof. Isabelle Mansuy, Ph.D

(University of Zurich and ETH Zurich, Switzerland)

Isabelle Mansuy is Associate Professor in Molecular Cognition at the Medical Faculty of the University Zürich, and the Swiss Federal Institute of Technology in Zürich (ETHZ). She completed a PhD in Developmental Neurobiology at the Friedrich Miescher Institute in Basel, Switzerland and the Université Louis Pasteur Strasbourg, France, then a postdoctoral training in the lab of Eric Kandel at the Center for Learning and Memory at Columbia University in New York. She was appointed Assistant Professor in Neurobiology at the ETHZ in Dec 1998. Her research examines the epigenetic basis of complex brain functions and focuses in particular, on cognitive functions and behavior in mammals. Her work revealed the existence of molecular suppressors of learning and memory in the adult mouse brain, and identified the Ser/Thr protein phosphatases calcineurin and PP1 as such suppressors. It demonstrated their importance in cognitive defects associated with aging, Alzheimer’s disease and neurodegeneration. It also revealed their role in chromatin remodeling in the adult brain, and in the epigenetic control of memory formation and synaptic plasticity. Isabelle Mansuy’s research also examines the mechanisms underlying the influence of detrimental environmental factors on behavior across generations. This work recently demonstrated that early stress in mice induces depression and impulsivity, and impairs social skills and cognitive functions, and that these behavioral symptoms are transmitted across several generations. It showed that epigenetic mechanisms involving DNA methylation are associated with the inheritance of the behavioral defects. This research is pluridisciplinary and combines genetically and environmentally modified animal models, epigenetic methods, molecular, behavioral, electrophysiological, proteomic and imaging techniques.
Isabelle Mansuy is member of the Swiss Academy of Medical Science, the Research Council of the Swiss National Foundation, the Research Council of the Fyssen Foundation and EMBO. She is acting in multiple review boards including at the European Neuroscience Institute Göttingen, the German Federal Ministry of Education and Research, CNRS, etc. She is chief co-editor of BioMolecular Concepts, and member of the editorial board member of Hippocampus, Neurobiology of Diseases, Frontiers in Behavioral Neurosciences, Biology of Mood and Anxiety Disorders, and Frontiers in Epigenomics. She co-authored several reviews and books in the field of molecular cognition and neuroepigenetics.

Epigenetics of Complex Behaviors and their Inheritance in Mammals
Isabelle M. Mansuy
Brain Research Institute, University/ETH Zürich, Winterthurerstrasse 190, Zürich.
The development and expression of behaviors in mammals are strongly influenced by environmental factors. When favorable and positive, these factors facilitate appropriate responses and allow normal behaviors, but when adverse and negative, they can lead to behavioral alterations. Stressful and traumatic events early in life are particularly negative risk factors that can induce behavioral and psychiatric conditions such as depression, personality disorders and antisocial behaviors. Such disorders can further not only affect the individuals directly exposed to trauma, but they can also be transmitted and similarly expressed in the following generations.
The mechanisms underlying the etiology and inheritance of behavioral symptoms induced by early traumatic stress have been proposed to involve epigenetic processes, but remain undefined. This talk will present an experimental model of early traumatic stress in mice and provides initial evidence for the contribution of epigenetic mechanisms to the impact of negative factors on behavior across generations. This model shows that chronic and unpredictable maternal separation combined with maternal stress causes depressive and impulsive behaviors, social withdrawal and cognitive defects in adult mice, and that these symptoms are transmitted to the following offspring across several generations. It further shows that these alterations are associated with persistent changes in DNA methylation in the promoter-associated CpG island of several genes, both in the germline of the stressd animals and in the brain of the offspring. These findings suggest the implication of epigenetic processes in the impact of negative environmental conditions on behavior.

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Marcus E Pembrey , M.D., Ph.D

(University College London, UK)
M.Pembrey @

Professor Marcus Pembrey, a retired clinical geneticist, is Emeritus Professor of Paediatric Genetics at the Institute of Child Health, University College London, Visiting Professor of Paediatric Genetics at the University of Bristol and Fellow of the UK Academy of Medical Sciences.  Marcus was previously Professor of Paediatric Genetics  and Vice-Dean at University College London’s Institute of Child Health , consultant clinical geneticist at Great Ormond Street Hospital for Children London and Consultant Advisor in genetics to the Chief Medical Officer at the UK Government ‘s Department of Health.  A past president of the European Society of Human Genetics, he co-founded the International Federation of Human Genetic Societies. His research into rare genetic syndromes showing unusual patterns of inheritance, included proposing permutations in Fragile X and establishing Angelman syndrome as an imprinting disorder. In 1988 he helped Professor Jean Golding establish the Avon Longitudinal Study of Parents and Children (ALSPAC) in Bristol, being its Director of Genetics until 2005. This is widely regarded as the most comprehensive general population birth cohort in the world with a cell-lined backed DNA bank on over 10,000 participants, their mothers and many fathers.  ALSPAC permits the study of interactions between genetic variation and the social and physical environment during development and how these impact on future health and wellbeing, including the next generation.  His current research focus is on environmental epigenomics  and transgenerational responses.

Human Transgenerational Responses.
Marcus Pembrey1,2, Lars Olav Bygren3,6, Gunnar Kaati4, Sören Edvinsson5, Kate Northstone2, The ALSPAC Study Team2, Michael Sjöström6, Jean Golding2.
1Clinical and Molecular Genetics Unit, Institute of Child Health, University College London, England; 2Avon Longitudinal Study of Parents and Children, Bristol University, England; 3Department of Community Medicine and Rehabilitation, Social Medicine, Umeå University, Sweden; 4Department of Public Health and Clinical Medicine, Umeå University, Sweden; 5Demographic Database, Umeå University, Sweden; 6Department of Biosciences, Preventive Nutrition, Karolinska Institute, Sweden.
Transgenerational effects of maternal and even grand-maternal nutrition or other environmental ‘exposures’ are to be expected, although unpicking the influences is difficult. Effects down the male line were not expected because a novel inheritance mechanism would have to be postulated if social patterning and other confounders can be excluded. We have reported earlier historical associations of longevity and diabetic deaths with paternal ancestors’ food supply in mid childhood (Bygren LO et al Acta Biotheoret. 2001;49:53, Kaati G et al EJHG 2002;10:682). Using the Avon Longitudinal Study of Parents and Children (ALSPAC, we identified 166 fathers who reported starting smoking before age 11 years and showed, after correcting for confounders, that their sons (but not daughters) had a greater body mass index at 9 years than offspring of fathers with later onset of smoking. Sex-specific transmissions were also shown in two of three historical Överkalix cohorts from northern Sweden; paternal grandfather’s food supply was only linked to the mortality rate of grandsons, whilst paternal grandmother’s food supply was only associated with the granddaughters’ mortality rate (Pembrey et al EJHG 2006;14:159. Senn 2006 & Bygren et al EJHG 2006;14:1149). This pattern creates a situation that is ‘internally controlled’ for social patterning confounders down to the fathers. Further analysis adjusting for the early-life social circumstances of the probands (grandchildren) themselves shows that the male line transgenerational effects persist (Kaati et al EJHG 2007;15:784). These transgenerational effects were observed with exposure only at specific periods during the paternal ancestor’s development to 20 years: mid childhood (both grandparents) and fetal/infant life (grandmothers), but not during either grandparent’s puberty. Overall the patterns suggest that an evolved transgenerational response mechanism has been triggered. Curious sex-specific transmissions are being observed in experimental animal studies.
It is early days in the study of male-line transgenerational responses in humans, but some coherence is emerging with respect to observed outcomes. They have features of the Metabolic Syndrome which some regard as a ‘mal-adaptation’ to modern lifestyles. In addition to the cardiovascular and diabetic risks observed in the Överkalix cohort and the ALSPAC data linking mid childhood paternal smoking with raised body mass index in sons, a Taiwan study of paternal betel nut (Areca catechu) chewing linked this to early onset metabolic syndrome in the non-chewing offspring (Chen et al Am J Clin Nutr 2006; 83: 688). It is possible that genotoxic, nutritional, or ‘uncertainty’ stress triggers a default ‘survival’ mode of gene expression in descendants.
Currently the mediating molecular mechanisms are unknown. We hypothesise that the non-recombining region of the Y chromosome (and possibly the X) can preferentially transmit environmentally-induced states to the next generation(s).

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J. Andrew Pospisilik, PhD

(Freiburg, Germany)

J. Andrew Pospisilik studied Human Physiology at the University of British Columbia (Vancouver, Canada). There he joined Ray Pederson and documented for the first time the long-term benefits dipeptidyl peptidase IV inhibition on types-1 and -2 diabetes, including improvements in insulin-secretory function, insulin sensitivity, and β-cell turnover. Joining Josef Penninger as post-doc at IMBA (Vienna) in 2003, he exploited gene-targeting strategies in mice and tackled a long enigmatic link between mitochondrial dysfunction and diabetes and obesity. These findings broke dogma and changed our understanding of the etiology of insulin resistance. Next, Dr. Pospisilik completed the first genome-wide RNAi screen for obesity adult in drosophila, a work that lead to the discovery of Hedgehog signaling as one of the only pathways capable of differentially regulating the lineage commitment of brown and white adipose tissues in mammals. In 2010, he joined the MPI in Freiburg as an founding junior member of the institute’s Epigenetic Focus, the Max Planck Society’s commitment to foster excellence in Epigenetic research. Andrew is well recognized in the field with several highlights as must-read’s by the Faculty of 1000. He was nominated for Vienna’s “Future Prize”, and in 2011, he was awarded W2 (‘associate professor’ equivalent) by the Max Planck Society. He is the holder of numerous awards, patents, and prestigious grants. His lab is currently trying to understand the enigmatic role of a number of epigenetic control systems in the development of disease.

From fat flies to skinny mice: Genome-wide functional RNAi reveals distinct roles for developmental and chromatin-based regulation of obesity
Recent estimates place the global incidence of obesity beyond 1 billion by the year 2030. Perhaps most disturbing, rates of childhood obesity have more than doubled in the last decade. This rapid rise in early life incidence of obesity and the long-term health implications with respect to heart disease, diabetes and stroke, make obesity one of the world’s chief economic and health care challenges of the day. While numerous studies have established a genetic framework for our understanding of obesity, the contribution of several critical regulatory layers, in particular epigenetic regulation, remain poorly understood. In a recent genome-wide functional genetic screening approach, we have systematically interrogated the role of >10,000 genes for their role in obesity, pain and heart disease in adult flies in vivo. Perhaps the most intriguing finding has been the striking enrichment of developmental and chromatin regulatory genes in all three disparate disease states. Here, I will present our latest efforts to translate these findings to the mouse, systematically address the role of developmental and chromatin regulatory systems in multiple metabolic pathologies.

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Sam El-Osta. Ph.D


Associate Professor Sam El-Osta is a Senior Research Fellow at the Human Epigenetics and Epigenomics Profiling Centre for the study of Diabetes Complications and other Human Diseases at the Baker Heart Research Institute in Melbourne. Dr El-Osta has dual appointments at the Department of Medicine at Monash University and at the Department of Physiology at the University of Melbourne. His ongoing research is currently funded with a number of international and national grants and is a principal investigator on a number of ongoing funded projects. His independent research in Australia was rewarded in 2006 when he was named Australian Society for Medical Research “Medical Researcher of the Year” for research on the paradigm of epigenetic changes in human disease and more received the inaugural JDRF research award for type 1 diabetes in 2009 for his research into persistent epigenetic changes.

Sensing gene-regulatory hyperglycemic changes vascular endothelial cells Assam El-Osta1,2,4,5
1Epigenetics in Human Health and Disease Laboratory,
2Epigenomic Profiling Facility,
3JDRF Danielle Alberti Memorial Centre for Diabetic Complications, Baker IDI Heart and Diabetes Institute, The Alfred Medical Research and Education Precinct, Melbourne, Victoria, 3004, Australia
4Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
5Faculty of Medicine, Nursing and Health Sciences, Monash University, Victoria, Australia
Despite the remarkable advances in uncovering the importance of intensive glucose control in the development of diabetic complications, a fundamental question still remains regarding the specific molecular events mediating past glycemic control and long-term future benefits, a phenomenon now often referred to as hyperglycemic memory or the “legacy effect”. For more than twenty years several multicenter clinical trials have popularised the concept that glucose is a demonstrable determinant to the development of diabetic complications indicating the prolonged benefit of intensive therapy and lasting damage of conventional therapy. The inaugural Diabetes Control and Complications Trial (DCCT, 1982-93) and the follow-up study, Epidemiology of Diabetes Interventions and Complications (EDIC, 1994-2006) have highlighted key principles that address the concept glycemic control with the consequence of long-term complications. The endothelial cell is considered a key vascular cell capable of sensing changes in glucose concentrations because of its location in the blood vessel wall. Thus, these cells are viewed as critical in transmitting signalling cues to underlying layers of the vessel wall by altering gene expression patterns. Remarkably, very little is known about how glucose per se influences gene expression with recent studies demonstrating that glucose, probably via intermediates such as reactive oxygen species and methylglyoxal, as a result of mobilization of key methyltransferase enzymes mediate gene expression changes. The present study builds on these findings and extends the role of chromatin modifications emphasizing that gene regulatory events in the vasculature are characteristic of diabetes. We show that transcriptional mechanisms involved in gene regulation mediated by glucose are dependent on specific methyltransferase enzymes showing a clear distinction on target genes and proteins important in the vasculature. We also demonstrate the importance of mapping chromatin modifications as well as defining the pattern of genomic methylation and build a human map of hyperglycemic response to better understand the increased risk of cardiovascular disease and the legacy effect.

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Session 5,
Epigenetics in the Complex Biological Systems (I) (Morning, 22 April)

Jing-Dong Jackie Han,Ph.D


Dr Jing-Dong Jackie Han obtained Ph.D. degree from Albert Einstein College of Medicine. She had her postdoctoral training at The Rockefeller University and Dana-Farber Cancer Institute. In 2004, she became an investigator/professor at the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences. She is currently a director of the CAS-Max Planck Partner Institute for Computational Biology. Her research focuses on the topology, dynamics and structure inference of molecular networks. She was awarded the Chinese Academy Sciences Hundred Talent Plan and NSFC Outstanding Young Scientist Award in 2006, and the Hundred Talent Plan Outstanding Achievement Award in 2009.

Epigenetic Regulation of Aging
CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Yueyang Road, Shanghai, 200031, China
Epigenetic modifications are thought to be important for gene expression changes during development and aging. However, besides the Sir2 histone deacetylase in somatic tissues and H3K4 trimethylation in germlines, there is scant evidence implicating epigenetic regulations in aging. We found that progressive increases in gene expression and loss of H3K27me3 on IIS components are due, at least in part, to increased activity of the H3K27 demethylase UTX-1 during aging. RNAi of the utx-1 gene significantly extended the mean lifespan of C. elegans through decreasing IIS activity and leading to a more "naive" epigenetic state. Like stem cell reprogramming, our results suggest that reestablishing epigenetic marks lost during aging might help “reset” the developmental age of animal cells.
So far, whole genome-wide evidence for the epigenetic regulation to the aging plasticity has largely not been investigated. We employed the ChIP-seq approach to examine the active histone modification mark H3K4me2 in prefrontal cortex tissue (PFC) of Rhesus macaque at different ages and identified consistent age-dependent global changes of the H3K4me2 modification levels at the promoter and enhancer regions during development and aging, implicating environmental history of the cells memorized at the epigenomic level.

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Howard Cedar, M.D., Ph.D

Hebrew University

Howard Cedar was born in N.Y., studied mathematics at MIT and received M.D. and Ph.D. degrees from NYU in 1970.  After a short period of postdoctoral research at the NIH, he moved to Israel and joined the Faculty of Medicine at the Hebrew University where he is now a full Professor.  Together with Aharon Razin, he discovered the mechanism of DNA methylation that is responsible for controlling genes involved in development and explained the biochemistry, molecular biology and function of this unique epigenetic modification.  His research is now directed towards understanding how methylation patterns are formed in vivo and in deciphering the sequence code that regulates this process.

Programming DNA Methylation During Development
Hebrew University, Jerusalem, ISRAEL
DNA methylation derived from the gametes is probably erased during early development and a bimodal pattern of methylation is then re-established at about the time of implantation. While this basic profile is maintained throughout development, targeted demethylation and de novo methylation events during the formation of specific cell lineages. The orchestration of this process takes place according to well-defined rules and is probably directed by sequence information within the DNA itself. Using genetic and epigenetic manipulations in tissue culture and transgenic mice, we have attempted to decipher the mechanisms involved in setting up methylation patterns at different stages of development, thus revealing the factors required for specificity as well as the enzymatic machinery for carrying out the reactions. Our studies also shed light on methylation changes that occur during somatic-cell reprogramming.

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Hiroyuki Sasaki, M.D., Ph.D

(Fukuoka, Japan)

Hiroyuki Sasaki is a Distinguished Professor and Vice Director at Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. He graduated from Kyushu University Medical School in 1982 and obtained his Ph.D. in Medical Science from Kyushu University Graduate School in 1987. He served as an Assistant Professor at Institute of Genetic Information, Kyushu University, and then joined AFRC Institute of Animal Physiology and Genetics Research, and Wellcome/CRC Institute of Developmental Biology and Cancer Research, Cambridge, UK, as an Overseas Research Fellow. He was appointed as an Associate Professor at Institute of Genetic Information, Kyushu University, in 1993 and then moved to National Institute of Genetics, Mishima, Japan, as a tenured Professor in 1998. Dr. Sasaki’s research is focused on the regulation of the mammalian epigenome in germ cells and in early embryos. He is particularly interested in DNA methylation and small RNA-based mechanisms and studies genomic imprinting as a model system to dissect the regulatory mechanisms. He currently serves as the President of Japanese Society for Epigenetics, a Board member of Japan Society of Human Genetics, a Board member of Genetics Society of Japan, and an Editorial Board member for Human Molecular Genetics and Journal of Human Genetics. He was awarded the Japan Society of Human Genetics Award in 2009.

Identification of DNA methylation differences correlated with transcriptional divergence between humans and chimpanzees in chromosomes 21 and 22
Kei Fukuda, Kenji Ichiyanagi, Yoichi Yamada, Yasuhiro Go, Toshifumi Udono, Seitaro Wada, Toshiyuki Maeda, Hidenobu Soejima, Naruya Saitou, Takashi Ito, and Hiroyuki Sasaki.
Division of Epigenomics, Medical Institute of Bioregulation, and Epigenome Network Research Center, Kyushu University, Japan
The phenotypic divergence between humans (Homo sapiens) and chimpanzees (Pan troglodytes) is generally attributed to the 1.2% difference in genomic sequence. Besides changes in protein structure and function, changes in gene expression likely have an important role in phenotypic diversification. Thus, in addition to genetic differences, epigenetic differences may contribute to inter-specific phenotypic differences in conjunction with or independently from genetic changes. We here report a survey of DNA methylation differences between humans and chimpanzees in chromosomes 21 and 22, which identified sixteen species-specific differentially methylated regions (S-DMRs). Most S-DMRs are tissue-specific and arise late in development, and many of them are associated with genes, notably in CpG islands (CGIs) or CGI shores. Moreover, we find S-DMRs clearly correlated with differences in promoter activity and alternative splicing. Interestingly, some of the S-DMRs are located in disease-related genes such as APP (Alzheimer’s disease), KCNJ15 (diabetes) and MN1 (tumor). By comparing the methylation status and genomic sequence of the S-DMRs with those of other great apes, we present evidence supporting genetic origin of some of the S-DMRs. Our findings suggest that epigenetic changes caused by genetic changes can contribute to transcriptional diversification in evolution.

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Yijun Qi, Ph.D

(Beijing, China)

Yijun Qi is an Associate Investigator at the National Institute of Biological Sciences, Beijing, China. He received his B.S. in Plant Pathology from Nanjing Agricultural University in 1995 and his Ph.D. in Molecular Biology from Zhejiang University in 2001. Following postdoctoral research with Dr. Biao Ding at the Ohio State University and Dr. Greg Hannon at Cold Spring Harbor Laboratory, he joined the faculty of the National Institute of Biological Sciences, Beijing in 2006.  Dr. Qi’s research is focused on the mechanism of small RNA pathways and the biological roles of small RNAs in plants. Recently, his lab revealed how plant small RNAs are sorted into effector complexes and discovered a novel class of miRNAs that mediates DNA methylation.

A Role for Small RNAs in DNA Double-Strand Break Repair
Wei Wei1,3, Zhaoqing Ba2,3, Min Gao4, Yang Wu3, Yanting Ma3, Simon Amiard6, Charles I. White6, Jannie Michaela Rendtlew Danielsen4 , Yun-Gui Yang4, and Yijun Qi3,5 1Graduate Program, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; 2College of Life Sciences, Beijing Normal University, Beijing 100875, China; 3National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China ; 4Genome Structure & Stability Group, Disease Genomics and Individualized Medicine Laboratory, Beijing Institute of Genomics, Chinese Academy of Sciences, No.7 Beitucheng West Road, Chaoyang District, Beijing 100029, P.R.China; 5School of Life Sciences, Tsinghua University, Beijing 100084, China; 6Génétique, Reproduction et Développement, Unité Mixte de Recherche Centre National de la Recherche Scientifique 6247, Clermont Université, Institut National de la Santé et de la Recherche Médicale U931, Aubiere 63177, France
Eukaryotes have evolved complex mechanisms to repair double-strand breaks (DSBs) through coordinated actions of protein sensors, transducers, and effectors. Here we show that ~21-nucleotide small RNAs are produced from the sequences in the vicinity of DSB sites in Arabidopsis and in human cells. We refer to these as diRNAs for DSB-induced small RNAs. In Arabidopsis, the biogenesis of diRNAs requires the PI3 kinase ATR, RNA polymerase IV (Pol IV), and Dicer-like proteins. Mutations in these proteins as well as in Pol V cause significant reduction in DSB repair efficiency. DiRNAs are recruited by Argonaute 2 (AGO2) in Arabidopsis to mediate DSB repair. Knock down of Dicer or Ago2 in human cells reduces DSB repair. Our findings reveal a conserved function for small RNAs in the DSB repair pathway. We propose that diRNAs may function as guide molecules directing chromatin modifications or the recruitment of protein complexes to DSB sites to facilitate repair.

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Soo-Jong Um, Ph.D

(Seoul, Korea)

Soo-Jong Um, PhD, Professor of Department of Bioscience and Biotechnology, Sejong University, Korea. Dr. Um graduated Seoul National University and received Ph.D. from Johns Hopkins University, Department of Biochemistry in 1993, based on the biochemical characterization of DNA replication. Afterwards, he moved to IGBMC in France for his postdoctoral research on transcriptional regulation of nuclear hormone receptors. Following serving as research associate at Catholic Medical College in Korea for three years, he was appointed as an Assistant Professor at Sejong University in 1999. Dr. Um has investigated the molecular mechanisms of eukaryotic transcription factors such as p53, IRF, and nuclear receptors. Currently, his research focuses on the epigenetic mechanisms mediated by nuclear receptors and histone modifications. Dr. Um has served as a chairman of Epigenomics section of the Korean Society for Molecular and Cellular Biology (2009), an organizer of the Korea-Japan Epigenomics Meeting (2009), and editors of several journals: Experimental Molecular Medicine, World J. of Biological Chemistry, and International J. of Biochemistry and Molecular Biology (2011-)

Epigenetic role of Additional Sex Comb-like (ASXL) family in nuclear hormone receptor signaling
Soo-Jong Um
Department of Bioscience & Biotechnology, Sejong University, Seoul 143-747, Korea
Additional sex comb-like 1 (ASXL1), a mammalian homolog of Drosophila ASX, was originally identified in my laboratory as a protein that interacts with the nuclear receptor RAR in the presence of retinoic acid (RA). Our previous studies indicated that ASXL1 functions as either coactivator or repressor of RAR in a cell-specific manner (JBC 2006; JBC 2010). Recently, we found that ASXL1 and ASXL2, a paralog of ASXL1, reciprocally regulate the transcriptional activity of other nuclear receptor PPAR, and thus modulate the PPAR-induced adipogenesis (JBC 2011). To understand the molecular mechanism underlying this opposite regulation in detail, we purified the ASXL1 and ASXL2 complexes which are composed of various histone modifying enzymes and chromatin proteins. Factors common to both ASXLs were BAP1, LSD1, PRMT5, OGT, HCF-1, and WD45. Of note, HP1, PKM2, RVB1/2, and TIF1 were specific for ASXL1, while histone H3K27 demethylase UTX and H3K4 methyltransferase MLL were for ASXL2. Complex profiling of ASXL2 and its expression in ERα-positive breast cancer cells prompted us to determine the role in ERα activation associated with chromatin regulation. Further, the reduced proliferative potential of MCF-7 cells under ASXL2 knock-down condition in BALB/c mice, and the highly correlated expression of ERα and ASXL2 in human breast cancer patients implicate the role of ASXL2 in ERα-positive breast cancer. Finally, we dissected the functional significance of the interaction between ASXL1 and BAP1. Our studies present a possible role of BAP1 as a histone deubiquitinase in concert with ASXL1 in maintaining the pluripotency and surveillance of mammalian stem cells prior to committing RA-induced differentiation.

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Yuin-Han Jonathan Loh, Ph.D


Yuin-Han Jonathan Loh is a Principle Investigator at the Institute of Medical Biology, and an Adjunct Assistant Professor at the National University of Singapore. He received his B.Sc. in Cellular and Molecular biology with First class honours from the National University of Singapore (2003). He did his Ph.D. research in the laboratory of Dr Ng Huck Hui at the Genome Institute of Singapore where he elucidated the link between the genetic and epigenetic regulation mechanisms controlling ES cells. This resulted in the discovery of two chromatin modifiers that are necessary in determining the ES cell fate.
He then started his Postdoctoral fellowship with Professor George Q. Daley at the Howard Hughes Medical Institute in the Children’s Hospital Boston at Harvard Medical School. There, he focused on developing innovative technologies to engineer defined factor cell fate reprogramming. Jonathan shown for the first time that terminally differentiated human blood cells can be epigenetically reprogrammed to pluripotent stem cells. Jonathan has recently been awarded the prestigious A*STAR Investigatorship Award and had started the Epigenetics and Cell fates Laboratory at the Institute of Medical Biology. The laboratory is interested in dissecting the genetic and epigenetic mechanisms regulating cell fate changes, while developing novel tools and strategies in deriving differentiated cell types via defined factors reprogramming. Jonathan is a recipient of several awards including the Philip Yeo prize (2008) Singapore Young Scientist award for Biological and Biomedical Sciences (2009), and the Singapore Youth award for Science and Technology (2010). He is currently on the Editorial board of American Journal of Molecular Biology and World Journal of Stem Cells

Systematic analysis of defined factor reprogramming
The epigenome of differentiated cells are remarkably plastic. Cellular reprogramming or lineage conversions can be effected simply through the introduction of defined transcription factors. The ability to generate autologous, patient-specific stem cells offers unprecedented potential for disease research, drug screening, and regenerative medicine. We have performed comprehensive systematic analysis of the transcriptome, genome, epigenome and proteomes, evaluating multiple partially and fully reprogrammed hiPSC, hESC and somatic lines. Our study provides new insights into the molecular mechanisms during the process of iPSC reprogramming.These data profiled the genetic and epigenetic regulatory network during the initial stage of reprogramming and revealed new features of the transcriptional landscapes.

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Yijun RUAN, PhD


Dr Ruan is a genomic researcher at the Genome Institute of Singapore, A*STAR. His research interest is to elucidate the structure and dynamics of functional DNA elements in the human genomes. His strategy is to develop innovative genomic technologies and apply them to address fundamental biological questions pertinent to human disease. To this end, he and his group have developed a series of paired-end-tag sequencing (PET) technologies to investigate the mechanisms of gene transcription regulation, including RNA-PET for transcriptome and ChIP-PET/ ChIA-PET for chromatin higher-order organization. His main biological focus is on genome functions and genome variations in cancer and stem cells.

3D Chromosomal Architectures and Transcriptional Regulation
Genomes are known to be organized into 3-dimensional (3D) conformation in vivo through interactions with protein factors for nuclear process such as transcription, and DNA elements separated by long genomic distances are known to functionally interact. However, the details of this view are largely unknown. To study long-range chromatin interactions mediated by protein factors, we developed Chromatin Interaction Analysis using Paired-End-Tag sequencing (ChIA-PET), and applied ChIA-PET analysis to detect all chromatin interactions involved in gene transcription regulation that are associated with RNA polymerase II (RNAPII). In these analyses, we identified widespread promoter-centered interaction including intra-, extra-, and inter-genic chromatin interactions, of which the vast majority was intra-chromosomal (98% of all interactions). Many interactions further congregate into complex interaction structures. While some genes were involved in “single-gene” interactions (enhancer-promoter interactions), surprisingly, large number of genes were involved in “multi-gene” interaction complexes including promoter-promoter and enhancer-promoter interactions, some of which could span up to several megabases. The extensive promoter-promoter interactions are in principle akin to the bacterial operon as a mechanism for coordinated transcriptional regulation of related proximal genes, suggesting the possibility of a chromatin-based operon mechanism (chro-operon or chroperon) for spatiotemporal regulation of gene transcription in eukaryotic nuclei. We demonstrated that genes in chroperons could transcribe cooperatively, and discovered that promoters could influence each other, implying higher-order combinatorial complexity of transcriptional controls. Overall, our studies provided new dimension of combinatorial controls of gene transcription within the context of chromatin looping architecture in eukaryotic genomes, and paved the way towards presenting the 3D topographic maps of the human genomes.

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Dirk Schübeler,Ph.D

(Basel, Switzerland)

Dirk Schübeler is a senior group leader at the Friedrich Miescher Institute for Biomedical Research in Basel (Switzerland) and adjunct Professor at the University of Basel. After receiving his PhD in Biology from the Technical University of Braunschweig (Germany) in 1998 he did postdoctoral training with Mark Groudine at the Fred Hutchinson Cancer Center (Seattle, USA) studying globin gene regulation. In 2003 he started his own lab in Basel pursuing his interest in the nature of "chromatin structure" and its correlation with gene activation and silencing. His research aims at further understanding how nuclear events influence the expression phenotype in higher eukaryotes and how they are propagated during cell division. His group applies functional genomics approaches to gain a comprehensive view on genome and epigenome regulation. The work has led to the first genome-wide maps of replication timing and histone modifications in eukaryotes. His group has pioneered approaches to study DNA methylation at the level of the genome. His recent work revealed basic principles of the important crosstalk between DNA sequence and epigenome structure. Dirk Schübeler is an elected member of EMBO and recipient of an award grant of the European Research Council. He serves on the editorial boards of PLoS Genetics, EMBO, EMBO reports and BMC Biology.

Genetic determinants of epigenetic repression
Dirk Schübeler
Friedrich Miescher Institute for Biomedical Research, Basel, 4053, Switzerland
Chromatin and DNA modifications have emerged as a critical component for gene regulation in higher eukaryotes yet how these epigenetic variables are targeted to specific sites of the genome is still poorly understood.
We have generated global maps of DNA methylation, histone modifications and replication in higher eukaryotes using stem cell differentiation as a dynamic cellular model for pluripotency, lineage commitment and terminal differentiation.
This comprehensive analysis allowed us to identify genomic sites that change their epigenetic status cell-state specific. Based on the resulting datasets we generate models how these epigenetic variables are targeted, which we test by genetic perturbation of involved modifiers and mutation of putative recruiting elements.
Our results suggest that DNA sequence of regulatory regions is a key determinant of dynamic chromatin states, a finding, which will be discussed in the light of current models of the function of epigenetic restriction during development.

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Session 6,
Epigenetics in the Complex Biological Systems (II) (Afternoon, 22 April)

Craig L. Peterson, Ph.D.

(Boston, USA)

Craig L. Peterson is a tenured Professor and Vice-Chair in the Program in Molecular Medicine at the University of Massachusetts Medical School, Worcester, MA, USA. He received his B.S. in Molecular Biology from the University of Washington in 1983 and his Ph.D. in Molecular Biology from the University of California, Los Angeles in 1988. Notably, he trained with Hal Weintraub in the early ‘80s, providing his first exposure to issues related to chromatin dynamics. Following postdoctoral research with Ira Herskowitz at the University of California, San Francisco, he joined the faculty of the University of Massachusetts Medical School in 1992.  Dr. Peterson’s research is focused on the genetic and biochemical analyses of chromatin remodeling enzymes, chromatin higher order folding, and the role of chromatin dynamics in transcription, DNA repair, and DNA replication. His work led to the discovery and biochemical characterization of one of the first chromatin remodeling enzymes, SWI/SNF, and he has used methods such as native peptide ligation and sedimentation velocity analyses in the analytical ultracentrifugation to decipher the biochemical roles of histone modifications. Recent research focuses on the roles of chromatin dynamics in cellular pathways that control genome integrity. He is currently an Associate Editor at Molecular Cell, and serves on the Editorial Boards of Current Biology, Molecular and Cellular Biology, PloS Genetics, and Molecular Biology of the Cell.

Chromatin Dynamics and Genome Integrity
Nicholas Adkins1, Hengyao Niu2, Patrick Sung2, Craig L. Peterson1,3
1Program in Molecular Medicine, University of Massachusetts Medical School;2Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine;3Corresponding author
The repair of DNA double strand breaks (DSBs) is critical for the maintenance of genome integrity. Improperly repaired DSBs can lead to loss of genetic material, chromosomal duplications or translocations that can result in carcinogenesis1. Over the past few years, we have established in vitro and in vivo assays to dissect the process of recombinational repair of DSBs in the context of chromatin fibers. The first step in DSB repair by homologous recombination (HR) is conversion of the break into single-stranded intermediates by one of two identified resection pathways, exemplified by yeast Exo1 and Sgs1/Dna2 (note that Sgs1 is the yeast homolog of the human Bloom [BLM] helicase). We now report in vitro and in vivo studies that characterize the impact of chromatin dynamics on each resection pathway. Importantly, the helicase activity of yeast Sgs1 and its human homolog, BLM, is reduced on nucleosomal substrates. Furthermore, we find that activity of the Sgs1/BLM-dependent machinery requires a nucleosome-free gap adjacent to the DSB. We also report that resection by Exo1 is blocked by nucleosomes, and that processing activity can be partially restored by removal of the H2A/H2B dimers or incorporation of the histone variant H2A.Z. Our study suggests that each of the two DSB processing pathways require distinct chromatin remodeling events in order to navigate chromatin structure adjacent to a DSB, indicating complex interactions between chromatin dynamics and DNA repair by HR.

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Chunming Ding,Ph.D


Dr. Ding is currently a principal investigator and the director for the Epigenetics Centre at the Singapore Institute for Clinical Sciences. He was an assistant professor in the Faculty of Medicine at the Chinese University of Hong Kong from 2005-2008, and a research assistant professor in the Bioinformatics program at Boston University from 2003-2004. He obtained his Ph.D. degree in Bioinformatics from Boston University in 2003 and his MS degree in Biochemistry from Brandeis University in 2000. He has pioneered a number of technologies for sensitive, specific and quantitative analyses of DNA and RNA, and has successfully applied them in non-invasive prenatal diagnosis, cancer monitoring, and pathogen analysis using peripheral blood. His current research focuses on both basic and applied epigenetics. His group is using next generation sequencing technologies for biomarker discovery, as well as understanding the fundamental mechanisms for epigenetic regulation. His work has resulted in numerous publications in prestigious journals such as Science, Nature Medicine, Nature Biotechnology and PNAS with over 1,600 citations, and over 60 patent applications (14 granted).

The DNA methylome of the human placenta
The human placenta is an important organ connecting the fetus and the mother during pregnancy. For the developing fetus, it provides nutrients and gas exchange, and removes waste via the maternal blood. It also produces and releases a number of hormones and endocrines for both the fetus and the mother. During pregnancy, the placenta undergoes significant growth at various gestation stages. Defects in placenta development may lead to diseases such as preeclampsia, which may occur in about 5% of all pregnancies.
We quantitatively profiled the human placenta DNA methylome at single CpG resolution, using bisulfite conversion and high-throughput sequencing. With two sequencing lanes on the Illumina Solexa GAIIx system, we were able to quantify ~2 million individual CpG sites by bisulfite sequencing at 10X coverage or higher. Over 40% of these CpGs are outside of CpG rich regions such as CpG islands (CGIs) and CpG island shores (CGSs). These CpG sites covered about 75% of CGIs, 51% of CGSs and 81% of core promoters in the human genome with at least 3 CpG sites. Our long term goal is to understand the epigenetic component in placenta development and pathogenesis of placenta-associated diseases, as well as to identify potential diagnostic biomarkers.

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Yoo-Sun Noh, PhD

(Seoul, Korea)

Yoo-Sun Noh, PhD, plant molecular biologist, graduated from the Department of Biology at Seoul National University, Korea in 1989. He obtained his MS degree from Seoul National University in 1991 and his PhD degree from the University of Wisconsin-Madison, USA in 1998. He worked at the University of Wisconsin-Madison 1998-2003 as a postdoc and in Kumho Life & Environmental Science Laboratory, Korea 2003-2005 as a Principal Investigator. Since 2005, he has become an Assistant/Associate Professor in the School of Biological Sciences at Seoul National University. He has also become the Director of the Global Research Laboratory for Floral Regulatory Signaling at Seoul National University since 2006. In recent years, he has focused on floral regulatory signaling and chromatin-mediated or epigenetic control of plant development. Although his interest in epigenetics was initiated from his studies on flowering, he has expanded his interests in epigenetic field to other plant development or environmental signaling areas such as plant cell differentiation/dedifferentiation, plant immunity, light signaling, and seed dormancy/germination. Among these, seed dormancy is a long-term mysterious process for which molecular mechanisms are poorly understood. In this seminar, he will talk about epigenetic aspects of seed germination, which is a dormancy-breaking process.

Control of seed germination by posttranslational histone modification
School of Biological Sciences, Seoul National University, Seoul 151-747, Korea.
Seed germination, which distinguishes post-embryonic development from embryonic development, is one of the important developmental phase transitions in seed plants. For optimal survival, various environmental and endogenous factors should be monitored properly to determine appropriate timing for seed germination. Among environmental factors, light is perceived by phytochromes and promotes seed germination. Light-dependent activation of phytochromes modulates ABA and GA levels by regulating both their metabolic and signaling pathways. Several negative regulators of seed germination that act when phytochromes are inactive have been reported. However, neither positive regulators of seed germination nor direct mechanisms for the regulation of the hormonal levels have been reported. Here we report that two functionally redundant histone modifiers act as positive regulators of seed germination. We show that loss of these factors leads to reduced germination efficiency when red light pulse is treated. Our study also shows the control of some key germination genes and modification of their chromatins by these novel factors as well as a regulatory pathway involving them. Thus, our study demonstrates the epigenetic nature of light-dependent seed germination.

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Kinichi Nakashima, Ph.D


Dr. Nakashima is a Professor at Nara Institute of Science and Technology (NAIST), Nara, Japan. He received his Ph.D. in Chemistry from the Kyushu University, Fukuoka, Japan in 1995. He did postdoc at Osaka University and Tokyo Medical and Dental University (1995-1997) and became an assistant professor at Tokyo Medical and Dental University in 1998. He then became an associate professor at Kumamoto University  in 2000. He moved to the Salk Institute (Dr. Fred H Gage laboratory) and spent 2 years as a research fellow (2002-2004), and obtained the present position in 2004. Dr. Nakashima started his research regarding neural stem cell (NSC) fate specification by analyzing cell external cues (cytokines), but gradually became interested in cell internal program, i.e., Epigenetics. He first reported that DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain in 2001. He also found anti epileptic and HDAC inhibitor valproic acid dramatically induces neuronal differentiation of NSCs. Tanking advantage of this effect of valproic acid, Dr. Nakashima has recently developed a new method the treatment of spinal cord injury referred to as HINT (Hdac Inhibitor and NSC Transplantation) method in 2010. Thus, Dr. Nakashima ’s research is focused on the NSC regulation by epigenetic programs. He is currently serving as an editorial board member for Stem Cells and Current Stem Cell Research & Therapy.

Interplay between genes and the environment via epigenetic mechanisms in neural stem cells
Nara Institute of Science and Technology
The central nervous system (CNS) is composed of three major cell types – neurons, astrocytes, and oligodendrocytes– which differentiate from common multipotent neural stem cells (NSCs). This differentiation process is regulated spatiotemporally during the course of mammalian development. During mid-gestation, NSCs differentiate only into neurons. Generation of astrocytes is prevented at this stage, because astrocyte-specific gene promoters are methylated. Notch signaling is a conserved pathway from insects to mammals which contributes to cell-to-cell communication and controls cell fate determination in the CNS. We have previously shown that in the cortex of mouse embryo, Notch ligands are expressed in neuronally committed precursor cells and young neurons, and that Notch signaling is activated in neighboring NSCs. We have further demonstrated that the activation of Notch signaling pathway in mid-gestational NSCs induces expression of the transcription factor nuclear factor-I, which binds to astrocytic gene promoters, resulting in demethylation of astrocyte-specific genes. These findings have provided a mechanistic explanation for why neurons come first: committed neuronal precursors and young neurons potentiate remaining NSCs to differentiate into the next cell lineage, astrocytes. Oxygen levels in tissues including the embryonic brains are lower than those in the atmosphere. We here show that normoxic culture conditions delayed the timing of mid-gestational NSCs to acquire a differentiation potential into astrocytes as compared to hypoxic conditions. The primary oxygen sensor, hypoxia-inducible factor 1 (HIF1) plays a critical role to induce demethylation of astrocytic genes in mid-gestational NSCs by cooperating with Notch signaling pathway. Expression of constitutively active HIF1 and a hyperoxic environment respectively promoted and impeded astrocyte differentiation in the developing brain. Our findings suggest that hypoxia contribute to the appropriate scheduling of mid-gestational NSC fate determination.

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Session 4,
Epigenetics in Other Disease (Afternoon, 21 April)

Moshe Szyf, Ph. D.


Dr. Szyf is a James McGill and GlaxoSmithKline-CIHR Professor in Pharmacology at McGill University medical school in Montreal Canada. He is the founding co-director of the Sackler Institute for Epigenetics and Psychobiology at McGill and is a Fellow of the Canadian Institute for Advanced Research Experience-based Brain and Biological Development program. Szyf has worked on understanding the biochemical mechanisms and roles of DNA methylation in health and disease for the last thirty years.

The impact of early life experience on adult DNA methylation in the brain and in peripheral tissues.
Department of Pharmacology and Therapeutics, McGill University Montreal Quebec Canada
Although epidemiological data provides evidence that there is an interaction between genetics (nature) and the social and physical environments (nurture) in human development; the main open question remains the mechanism. The pattern of distribution of methyl groups in DNA is different from cell-type to cell type and is conferring cell specific identity on DNA during cellular differentiation and organogenesis. This is an innate and highly programmed process. However, recent data suggests that DNA methylation is not only involved in cellular differentiation but that it is also involved in modulation of genome function in response to signals from the physical, biological and social environments. We propose that modulation of DNA methylation in response to environmental cues early in life serves as a mechanism of life-long genome "adaptation" that molecularly embeds the early experiences of a child ("nurture") in the genome ("nature"). Data that supports this hypothesis from rodent, non-human primates, humans and population studies will be discussed. We will specifically focus on methylome-wide analyses of T cells in humans and nonhuman primates adults that reveal associations with early life adversity.

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Dr Huck-Hui, NG


Professor Huck-Hui NG is the Acting Executive Director of the Genome Institute of Singapore (GIS). Huck-Hui NG graduated from the National University of Singapore and obtained his PhD from the University of Edinburgh.  He spent the next few years working at the Harvard Medical School as a Damon Runyon-Walter Winchell research fellow.His lab is studying gene regulation in stem cells.  Specifically, his group is using genome wide approaches to dissect the transcriptional regulatory networks in embryonic stem cells and to identify key nodes in this network.  More recently, his lab has begun to investigate the reprogramming code behind the induction of pluripotency in somatic cells.  His research work has earned him several prestigious national accolades including the Singapore Youth Award 2005, the National Science Award 2007 and the President Science Award 2011.

Systems Biology of Stem Cells
Embryonic stem (ES) cells are characterized by their ability to self-renew and remain pluripotent. Transcription factors have critical roles in the maintenance of ES cells through specifying an ES-cell-specific gene expression program. Deciphering the transcriptional regulatory network that describes the specific interactions of these transcription factors with the genomic template is crucial for understanding the design and key components of this network. To gain insights into the transcriptional regulatory networks in ES cells, we use chromatin immunoprecipitation coupled to ultra-high-throughput DNA sequencing (ChIP-seq) to map the locations of sequence specific transcription factors. These factors are known to play different roles in ES cell biology. Our study provides new insights into the integration of these regulators to the ES cell-specific transcription circuitries. Collectively, the mapping of transcription factor binding sites identifies new features of the transcriptional regulatory networks that define ES cell identity. Using this knowledge, we investigate nodes in the network which when activated, will jump-start the ES cell-specific expression program in somatic cells.

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