调节人体内部生物钟的遗传机制一直是科学家研究的热点问题。近日，美国科学家发现了触发这一机制的化学“开关”。这是迄今为止得到的关于人体生理节奏（circadianrhythms）研究最明确的信息，为失眠以及其它相关疾病的药物治疗确定了精确的标靶。相关论文12月13日发表于《自然》（Nature）杂志上。
生理节奏是人体的内在追踪系统，它能预期环境变化，并调节到适当的时间。它调控着大量身体功能，如睡眠模式、荷尔蒙水平、代谢以及行为等。大约10%到15%的人类基因是由生理节奏进行调控的。打乱生物钟会深刻地影响人体的健康，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。
美国加州大学欧文分校药理学系Paolo Sassone-Corsi教授和同事曾于去年发现，触发生理节奏的基因CLOCK能够作为一种酶对染色质进行修正。在最新的研究中，他们发现，CLOCK的“伙伴”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。
Sassone-Corsi对于发现单个氨基酸就能激活生物钟机制感到非常惊讶。他说：“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。而在生物学中看到如此精确的分子调控总是让人心旷神怡。”
Sassone-Corsi表示，如果这个氨基酸修正受到了任何形式的损害，那么整个“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。（科学网梅进/编译）
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).
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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.
