SIRT1 regulates circadian clock gene expression through PER2 deacetylation
SIRT1 regulates circadian clock gene expression through PER2 deacetylation
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DOI：
10.1016/j.cell.2008.06.050
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发表时间：
2008-07-25
期刊：
影响因子：
64.5
通讯作者：
Schibler, Ueli
中科院分区：
文献类型：
--
作者：
Asher, Gad;Gatfield, David;Schibler, Ueli
哺乳动物的昼夜节律系统是由一个位于大脑视交叉上核的中央起搏器组成的，该起搏器与周围组织中无数的附属振荡器同步。节律产生机制被认为依赖于一个涉及积极和消极作用转录因子的反馈回路。BMAL1和CLOCK激活周期（Per）和隐色素（Cry）基因的表达，一旦Per和Cry蛋白积累到临界水平，它们就会与BMAL1-CLOCK异源二聚体形成复合物，从而抑制其自身基因的转录。在这里，我们发现SIRT1，一种NAD（+）依赖性蛋白去乙酰化酶，是几个核心时钟基因（包括Bmal1， Ror γ， Per2和Cry1）的高强度昼夜节律转录所必需的。SIRT1以昼夜节律的方式结合CLOCK-BMAL1，并促进PER2的去乙酰化和降解。考虑到SIRT1脱乙酰酶活性的NAD（+）依赖性，SIRT1很可能将细胞代谢与昼夜节律核心时钟电路联系起来。
The mammalian circadian timing system is composed of a central pacemaker in the suprachiasmatic nucleus of the brain that synchronizes countless subsidiary oscillators in peripheral tissues. The rhythm-generating mechanism is thought to rely on a feedback loop involving positively and negatively acting transcription factors. BMAL1 and CLOCK activate the expression of Period (Per) and Cryptochrome (Cry) genes, and once PER and CRY proteins accumulate to a critical level they form complexes with BMAL1-CLOCK heterodimers and thereby repress the transcription of their own genes. Here, we show that SIRT1, an NAD(+)- dependent protein deacetylase, is required for high-magnitude circadian transcription of several core clock genes, including Bmal1, Ror gamma, Per2, and Cry1. SIRT1 binds CLOCK-BMAL1 in a circadian manner and promotes the deacetylation and degradation of PER2. Given the NAD(+) dependence of SIRT1 deacetylase activity, it is likely that SIRT1 connects cellular metabolism to the circadian core clockwork circuitry.