Ottawa Institute of Systems Biology and Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ont., Canada K1H 8M5.
Hum Mol Genet. 2011 Feb 15;20(4):731-51. doi: 10.1093/hmg/ddq519. Epub 2010 Nov 30.
Mammalian circadian rhythms are synchronized to the external time by daily resetting of the suprachiasmatic nucleus (SCN) in response to light. As the master circadian pacemaker, the SCN coordinates the timing of diverse cellular oscillators in multiple tissues. Aberrant regulation of clock timing is linked to numerous human conditions, including cancer, cardiovascular disease, obesity, various neurological disorders and the hereditary disorder familial advanced sleep phase syndrome. Additionally, mechanisms that underlie clock resetting factor into the sleep and physiological disturbances experienced by night-shift workers and travelers with jet lag. The Ca(2+)/cAMP response element-binding protein-regulated microRNA, miR-132, is induced by light within the SCN and attenuates its capacity to reset, or entrain, the clock. However, the specific targets that are regulated by miR-132 and underlie its effects on clock entrainment remained elusive until now. Here, we show that genes involved in chromatin remodeling (Mecp2, Ep300, Jarid1a) and translational control (Btg2, Paip2a) are direct targets of miR-132 in the mouse SCN. Coordinated regulation of these targets underlies miR-132-dependent modulation of Period gene expression and clock entrainment: the mPer1 and mPer2 promoters are bound to and transcriptionally activated by MeCP2, whereas PAIP2A and BTG2 suppress the translation of the PERIOD proteins by enhancing mRNA decay. We propose that miR-132 is selectively enriched for chromatin- and translation-associated target genes and is an orchestrator of chromatin remodeling and protein translation within the SCN clock, thereby fine-tuning clock entrainment. These findings will further our understanding of mechanisms governing clock entrainment and its involvement in human diseases.
哺乳动物的昼夜节律通过视交叉上核（SCN）对光的每日重置来与外部时间同步。作为主生物钟起搏器，SCN 协调多个组织中不同细胞振荡器的时间。时钟计时的异常调节与许多人类疾病有关，包括癌症、心血管疾病、肥胖、各种神经紊乱和遗传性疾病家族性提前睡眠阶段综合征。此外，时钟重置因子的机制也会影响倒班工人和时差旅行者的睡眠和生理紊乱。钙/环腺苷酸反应元件结合蛋白调节的 microRNA，miR-132，在 SCN 内被光诱导，并减弱其重置或重新同步时钟的能力。然而，miR-132 调节的具体靶点及其对时钟重新同步的影响直到现在仍然难以捉摸。在这里，我们表明，参与染色质重塑（Mecp2、Ep300、Jarid1a）和翻译控制（Btg2、Paip2a）的基因是小鼠 SCN 中 miR-132 的直接靶点。这些靶点的协调调节是 miR-132 依赖的 Period 基因表达和时钟重新同步的基础：mPer1 和 mPer2 启动子与 MeCP2 结合并被其转录激活，而 PAIP2A 和 BTG2 通过增强 mRNA 降解来抑制 PERIOD 蛋白的翻译。我们提出，miR-132 被选择性地富集到与染色质和翻译相关的靶基因中，是 SCN 时钟内染色质重塑和蛋白质翻译的协调者，从而微调时钟重新同步。这些发现将进一步加深我们对调节时钟重新同步及其在人类疾病中作用的机制的理解。
