調(diào)節(jié)人體內(nèi)部生物鐘的遺傳機制一直是科學家研究的熱點問題,。近日，美國科學家發(fā)現(xiàn)了觸發(fā)這一機制的化學“開關(guān)”,。這是迄今為止得到的關(guān)于人體生理節(jié)奏（circadianrhythms）研究最明確的信息,，為失眠以及其它相關(guān)疾病的藥物治療確定了精確的標靶。相關(guān)論文12月13日發(fā)表于《自然》（Nature）雜志上,。
生理節(jié)奏是人體的內(nèi)在追蹤系統(tǒng),，它能預期環(huán)境變化，并調(diào)節(jié)到適當?shù)臅r間,。它調(diào)控著大量身體功能,，如睡眠模式、荷爾蒙水平,、代謝以及行為等,。大約10%到15%的人類基因是由生理節(jié)奏進行調(diào)控的。打亂生物鐘會深刻地影響人體的健康,，包括失眠,、抑郁、心臟病,、癌癥以及神經(jīng)退化紊亂等在內(nèi)的多種疾病都與此有關(guān),。
美國加州大學歐文分校藥理學系Paolo Sassone-Corsi教授和同事曾于去年發(fā)現(xiàn)，觸發(fā)生理節(jié)奏的基因CLOCK能夠作為一種酶對染色質(zhì)進行修正,。在最新的研究中,，他們發(fā)現(xiàn)，CLOCK的“伙伴”BMAL1蛋白上的單個氨基酸經(jīng)過修改,，會觸發(fā)與生理節(jié)奏有關(guān)的遺傳事件,。
Sassone-Corsi對于發(fā)現(xiàn)單個氨基酸就能激活生物鐘機制感到非常驚訝,。他說：“這個觸發(fā)作用如此精確，看起來它就像是一個可以用化合物進行調(diào)控的完美標靶,。而在生物學中看到如此精確的分子調(diào)控總是讓人心曠神怡,。”
Sassone-Corsi表示，如果這個氨基酸修正受到了任何形式的損害,，那么整個“開關(guān)”機制就會失效,，而這就有可能導致與生理節(jié)奏有關(guān)的疾病。目前,，他和研究小組正在測試能夠以此為標靶的抗體,。（科學網(wǎng)梅進/編譯）
原始出處:
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: [email protected]).
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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.
