PLoS Biology：中央和周边信号设定肝脏的生理时钟
任何经历时差的人，都会了解到生理时钟正常的重要性。人体经由视网膜光受体感应光线，再将讯息传递至脑部的视叉上核。周边组织的阶段调整可以让身体不同的生理时钟都能跟上相同的时间。将生理时钟同步化的方法，可能是间接经由依赖SCN的生理时钟来调整，例如摄食的周期或体温。但是，科学家还不清楚如何在分子层级将所有时钟同步调整。其中一个重要的问题是，周边组织中周期地表现的基因，是受到局部的生理时钟控制，还是由全身的生理时钟所控制。
根据一项发表于本周PLoS Biology中的新研究，研究人员Benoit Kornmann和Ueli Schibler等人研究肝脏的生理时钟，并试着回答这个问题。
为了确定这些基因是受到局部还是全身的控制，研究人员制造出一种小鼠品系，可以依照不同的研究条件，启动肝脏的生理时钟。
作者修改了一种名为REV-ERBa的转录因子，可抑制时钟基因Bmal1而关闭生理时钟的基因表现。经过修改的基因带有四环素敏感元素(TREs)，可以对于四环素和类似的抗生素产生反应。带有这个修改基因的小鼠与带有可以活化肝细胞中TREs的基因之小鼠交配。
牠们产下的子代被喂食类似四环素的doxycyline (Dox)，结果肝细胞中的REV-ERBa仍未活化，且Bmal1基因的功能正常。当转基因小鼠缺乏Dox 时，会过度表现REV-ERBa，且Bmal1是不活化的，因此有效地关闭了肝脏的生理时钟。
研究人员进一步发现，环境中的提示，包括升高的温度和氧化压力，会活化热休克因子1(HSF1)。当感应到代谢出现节律上的变化时，HSF1可调节节律基因mPer2的表现，而使周边组织的时钟同步化。
(资料来源 : Bio.com)
部分英文原文：
System-Driven and Oscillator-Dependent Circadian Transcription in Mice with a Conditionally Active Liver Clock
1 Department of Molecular Biology, University of Geneva, Geneva, Switzerland, 2 Department of Biochemistry, University of Geneva, Geneva, Switzerland, 3 Zentrum für Molekulare Biologie, Universität Heidelberg, Heidelberg, Germany, 4 Howard Hughes Medical Institute, Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois, United States of America
The mammalian circadian timing system consists of a master pacemaker in neurons of the suprachiasmatic nucleus (SCN) and clocks of a similar molecular makeup in most peripheral body cells. Peripheral oscillators are self-sustained and cell autonomous, but they have to be synchronized by the SCN to ensure phase coherence within the organism. In principle, the rhythmic expression of genes in peripheral organs could thus be driven not only by local oscillators, but also by circadian systemic signals. To discriminate between these mechanisms, we engineered a mouse strain with a conditionally active liver clock, in which REV-ERBα represses the transcription of the essential core clock gene Bmal1 in a doxycycline-dependent manner. We examined circadian liver gene expression genome-wide in mice in which hepatocyte oscillators were either running or arrested, and found that the rhythmic transcription of most genes depended on functional hepatocyte clocks. However, we discovered 31 genes, including the core clock gene mPer2, whose expression oscillated robustly irrespective of whether the liver clock was running or not. By contrast, in liver explants cultured in vitro, circadian cycles of mPer2::luciferase bioluminescence could only be observed when hepatocyte oscillators were operational. Hence, the circadian cycles observed in the liver of intact animals without functional hepatocyte oscillators were likely generated by systemic signals. The finding that rhythmic mPer2 expression can be driven by both systemic cues and local oscillators suggests a plausible mechanism for the phase entrainment of subsidiary clocks in peripheral organs.
英文全文链接：http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0050034
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