Center for Epigenetics and Metabolism; U1233 INSERM; Department of Biological Chemistry, School of Medicine, University of California, Irvine (UCI), Irvine, CA, USA.
Graduate School of Pharmaceutical Sciences, Department of Systems Biology, Kyoto University, Kyoto 606-8501, Japan.
Sci Adv. 2020 Dec 16;6(51). doi: 10.1126/sciadv.abc5629. Print 2020 Dec.
Circadian gene expression driven by transcription activators CLOCK and BMAL1 is intimately associated with dynamic chromatin remodeling. However, how cellular metabolism directs circadian chromatin remodeling is virtually unexplored. We report that the S-adenosylhomocysteine (SAH) hydrolyzing enzyme adenosylhomocysteinase (AHCY) cyclically associates to CLOCK-BMAL1 at chromatin sites and promotes circadian transcriptional activity. SAH is a potent feedback inhibitor of S-adenosylmethionine (SAM)-dependent methyltransferases, and timely hydrolysis of SAH by AHCY is critical to sustain methylation reactions. We show that AHCY is essential for cyclic H3K4 trimethylation, genome-wide recruitment of BMAL1 to chromatin, and subsequent circadian transcription. Depletion or targeted pharmacological inhibition of AHCY in mammalian cells markedly decreases the amplitude of circadian gene expression. In mice, pharmacological inhibition of AHCY in the hypothalamus alters circadian locomotor activity and rhythmic transcription within the suprachiasmatic nucleus. These results reveal a previously unappreciated connection between cellular metabolism, chromatin dynamics, and circadian regulation.
由转录激活因子 CLOCK 和 BMAL1 驱动的生物钟基因表达与动态染色质重塑密切相关。然而，细胞代谢如何指导生物钟染色质重塑实际上还未被探索。我们报告称，S-腺苷同型半胱氨酸（SAH）水解酶腺苷同型半胱氨酸酶（AHCY）在染色质位点周期性地与 CLOCK-BMAL1 结合，并促进生物钟转录活性。SAH 是 S-腺苷甲硫氨酸（SAM）依赖性甲基转移酶的强烈反馈抑制剂，AHCY 对 SAH 的及时水解对于维持甲基化反应至关重要。我们表明，AHCY 对于周期性的 H3K4 三甲基化、BMAL1 在染色质上的全基因组募集以及随后的生物钟转录是必不可少的。在哺乳动物细胞中耗尽 AHCY 或靶向药理学抑制 AHCY 会显著降低生物钟基因表达的振幅。在小鼠中，下丘脑 AHCY 的药理学抑制会改变昼夜节律性的活动和视交叉上核内的节律性转录。这些结果揭示了细胞代谢、染色质动力学和生物钟调节之间以前未被重视的联系。
