Department of Pharmacology, Unite 904 Inserm Epigenetics and Neuronal Plasticity, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
J Cell Sci. 2010 Nov 15;123(Pt 22):3837-48. doi: 10.1242/jcs.051649.
Circadian rhythms regulate a wide variety of physiological and metabolic processes. The clock machinery comprises complex transcriptional-translational feedback loops that, through the action of specific transcription factors, modulate the expression of as many as 10% of cellular transcripts. This marked change in gene expression necessarily implicates a global regulation of chromatin remodeling. Indeed, various descriptive studies have indicated that histone modifications occur at promoters of clock-controlled genes (CCGs) in a circadian manner. The finding that CLOCK, a transcription factor crucial for circadian function, has intrinsic histone acetyl transferase (HAT) activity has paved the way to unraveling the molecular mechanisms that govern circadian chromatin remodeling. A search for the histone deacetylase (HDAC) that counterbalances CLOCK activity revealed that SIRT1, a nicotinamide adenin dinucleotide (NAD(+))-dependent HDAC, functions in a circadian manner. Importantly, SIRT1 is a regulator of aging, inflammation and metabolism. 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 between energy balance, chromatin remodeling and circadian physiology. Here we review recent studies that support the existence of this link and discuss their implications for understanding mammalian physiology and pathology.
昼夜节律调节着广泛的生理和代谢过程。生物钟机制包括复杂的转录-翻译反馈环，通过特定转录因子的作用，调节多达 10%的细胞转录本的表达。这种基因表达的显著变化必然涉及染色质重塑的全局调控。事实上，各种描述性研究表明，组蛋白修饰在时钟控制基因（CCGs）的启动子上以昼夜节律的方式发生。发现时钟，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（HAT）活性，为揭示调节昼夜节律染色质重塑的分子机制铺平了道路。寻找与时钟活性相平衡的组蛋白去乙酰化酶（HDAC）的研究表明，烟酰胺腺嘌呤二核苷酸（NAD(+))依赖性 HDAC SIRT1 以昼夜节律的方式发挥作用。重要的是，SIRT1 是衰老、炎症和代谢的调节剂。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，这些发现为能量平衡、染色质重塑和昼夜生理之间的功能和分子联系建立了联系。在这里，我们回顾了支持这种联系存在的最新研究，并讨论了它们对理解哺乳动物生理学和病理学的意义。
