Bellet M M, Orozco-Solis R, Sahar S, Eckel-Mahan K, Sassone-Corsi P
Center for Epigenetics and Metabolism, School of Medicine, University of California, Irvine, Irvine, California 92697, USA.
Cold Spring Harb Symp Quant Biol. 2011;76:31-8. doi: 10.1101/sqb.2011.76.010520. Epub 2011 Dec 16.
The mammalian cell contains a molecular clock that contributes, within each organism, to circadian rhythms and variety of physiological and metabolic processes. The clock machinery is constituted by interwined transcriptional-translational feedback loops that, through the action of specific transcription factors, modulate the expression of clock-controlled genes. These oscillations in gene expression necessarily implicate events of chromatin remodeling on a relatively large, global scale, considering that as many 10% of cellular transcripts oscillate in a circadian manner. CLOCK, a transcription factor crucial for circadian function, has intrinsic histone acetyltransferase activity and operates within a large nuclear complex with other chromatin remodelers. CLOCK directs the cyclic acetylation of the histone H3 and of its own partner BMAL1. A search for the histone deacetylase (HDAC) that counterbalanced CLOCK activity revealed that SIRT1, a nicotinamide adenine dinucleotide (NAD(+))-dependent HDAC, functions in a circadian manner. Importantly, SIRT1 is a regulator of several metabolic processes and was found to interact with CLOCK and to be recruited to circadian promoters in a cyclic manner. As many transcripts that oscillate in mammalian peripheral tissues encode proteins that have central roles in metabolic processes, these findings establish a functional and molecular link among energy balance, chromatin remodeling, and circadian physiology.
哺乳动物细胞含有一个分子时钟，在每个生物体中，它对昼夜节律以及各种生理和代谢过程都有影响。时钟机制由相互交织的转录-翻译反馈环组成，这些反馈环通过特定转录因子的作用，调节时钟控制基因的表达。考虑到多达10%的细胞转录本以昼夜节律的方式振荡，基因表达中的这些振荡必然意味着在相对较大的全局范围内发生染色质重塑事件。CLOCK是一种对昼夜节律功能至关重要的转录因子，具有内在的组蛋白乙酰转移酶活性，并在与其他染色质重塑因子形成的大型核复合物中发挥作用。CLOCK指导组蛋白H3及其自身伴侣BMAL1的循环乙酰化。对与CLOCK活性相互平衡的组蛋白去乙酰化酶（HDAC）的研究发现，SIRT1是一种烟酰胺腺嘌呤二核苷酸（NAD(+)）依赖性HDAC，以昼夜节律的方式发挥作用。重要的是，SIRT1是几种代谢过程的调节因子，被发现与CLOCK相互作用，并以循环方式被招募到昼夜节律启动子上。由于在哺乳动物外周组织中振荡的许多转录本编码在代谢过程中起核心作用的蛋白质，这些发现建立了能量平衡、染色质重塑和昼夜节律生理学之间的功能和分子联系。
