Nature & Science：颠覆原有生物钟概念
在第二篇文章中，来自加州大学欧文分校（University of California, Irvine，生物谷注），日本东邦大学（Toho University）的研究人员在之前研究的基础上发现，激活生理节奏的基因CLOCK的绑定BMAL1蛋白上的单个氨基酸经过修改，会触发与生理节奏有关的遗传事件。
他们之前的研究证明CLOCK能作为一种酶对染色质进行修改，此次通过进一步分析，研究人员惊讶的发现这一单个氨基酸的改变能激活生物钟机制，文章通讯作者Paolo Sassone-Corsi表示，“这个触发作用如此精确，看起来它就像是一个可以用化合物进行调控的完美标靶。在生物学中看到如此精确的分子调控总是让人心旷神怡”，同时他也提出如果这个氨基酸的修改过程受到了任何形式的损害，那么整个分子开关机制就会失效，而这就有可能导致与生理节奏有关的疾病。目前，他和研究小组正在测试能够以此为标靶的抗体。
这是迄今为止得到的关于人体生理节奏研究最明确的信息，能为失眠以及其它相关疾病的药物治疗确定了精确的标靶。由于生物钟扰乱对于人体的健康有重要的影响，包括失眠、抑郁、心脏病、癌症以及神经退化紊乱等在内的多种疾病都与此有关。因此能找到精确的治疗标靶能解决许多问题，目前Sassone-Corsi等人下一步将研究以此为靶标的抗体。
原始出处：
Nature 450, 1086-1090 (13 December 2007) | doi:10.1038/nature06394; Received 15 July 2007; Accepted 16 October 2007
CLOCK-mediated acetylation of BMAL1 controls circadian function
Jun Hirayama1, Saurabh Sahar1, Benedetto Grimaldi1, Teruya Tamaru2, Ken Takamatsu2, Yasukazu Nakahata1 & Paolo Sassone-Corsi1
- Department of Pharmacology, School of Medicine, University of California, Irvine, 92697-4625 Irvine, California, USA
- Department of Physiology, Toho University, Faculty of Medicine, Tokyo 143-8540, Japan
Correspondence to: Paolo Sassone-Corsi1 Correspondence and requests for materials should be addressed to P.S.-C. (Email: psc@uci.edu).
Abstract
Regulation of circadian physiology relies on the interplay of interconnected transcriptional–translational feedback loops1, 2. The CLOCK–BMAL1 complex activates clock-controlled genes, including cryptochromes (Crys), the products of which act as repressors by interacting directly with CLOCK–BMAL13, 4. We have demonstrated that CLOCK possesses intrinsic histone acetyltransferase activity and that this enzymatic function contributes to chromatin-remodelling events implicated in circadian control of gene expression5. Here we show that CLOCK also acetylates a non-histone substrate: its own partner, BMAL1, is specifically acetylated on a unique, highly conserved Lys 537 residue. BMAL1 undergoes rhythmic acetylation in mouse liver, with a timing that parallels the downregulation of circadian transcription of clock-controlled genes. BMAL1 acetylation facilitates recruitment of CRY1 to CLOCK–BMAL1, thereby promoting transcriptional repression. Importantly, ectopic expression of a K537R-mutated BMAL1 is not able to rescue circadian rhythmicity in a cellular model of peripheral clock. These findings reveal that the enzymatic interplay between two clock core components6, 7 is crucial for the circadian machinery.
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