Sassone-Corsi Paolo
Department of Biological Chemistry, Center for Epigenetics and Metabolism, Unit 904 of INSERM, University of California, Irvine, Irvine, CA, 92697, USA
The circadian clock controls a large variety of neuronal, endocrine, behavioral and physiological responses in mammals. This control is exerted in large part at the transcriptional level on genes expressed in a cyclic manner. A highly specialized transcriptional machinery based on clock regulatory factors organized in feedback autoregulatory loops governs a significant portion of the genome. These oscillations in gene expression are paralleled by critical events of chromatin remodeling that appear to provide plasticity to circadian regulation. Specifically, the NAD-dependent deacetylases SIRT1 and SIRT6 have been linked to circadian control of gene expression. This and additional accumulating evidence shows that the circadian epigenome appears to share intimate links with cellular metabolic processes and has remarkable plasticity, showing reprogramming in response to nutritional challenges. In addition to SIRT1 and SIRT6, a number of chromatin remodelers have been implicated in clock control, including the histone H3K4 tri-methyltransferase MLL1. Deciphering the molecular mechanisms that link metabolism, epigenetic control and circadian responses will provide valuable insights towards innovative strategies of therapeutic intervention.
昼夜节律时钟控制着哺乳动物中各种各样的神经元、内分泌、行为和生理反应。这种控制在很大程度上是在转录水平上对以循环方式表达的基因施加的。一种基于反馈自动调节环中组织的时钟调节因子的高度专业化转录机制控制着基因组的很大一部分。基因表达中的这些振荡与染色质重塑的关键事件并行，这些事件似乎为昼夜节律调节提供了可塑性。具体而言，NAD依赖性脱乙酰酶SIRT1和SIRT6已与基因表达的昼夜节律控制相关联。这以及其他越来越多的证据表明，昼夜节律表观基因组似乎与细胞代谢过程有着密切联系，并且具有显著的可塑性，在应对营养挑战时会发生重编程。除了SIRT1和SIRT6之外，许多染色质重塑因子也与时钟控制有关，包括组蛋白H3K4三甲基转移酶MLL1。破译将代谢、表观遗传控制和昼夜节律反应联系起来的分子机制，将为创新治疗干预策略提供有价值的见解。
