Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Statistics, University of Michigan, 500 South State Street, Ann Arbor, MI 48109, USA.
Cell Rep. 2014 Feb 27;6(4):633-45. doi: 10.1016/j.celrep.2014.01.027. Epub 2014 Feb 13.
Synchrony of the mammalian circadian clock is achieved by complex transcriptional and translational feedback loops centered on the BMAL1:CLOCK heterodimer. Modulation of circadian feedback loops is essential for maintaining rhythmicity, yet the role of transcriptional coactivators in driving BMAL1:CLOCK transcriptional networks is largely unexplored. Here, we show diurnal hepatic steroid receptor coactivator 2 (SRC-2) recruitment to the genome that extensively overlaps with the BMAL1 cistrome during the light phase, targeting genes that enrich for circadian and metabolic processes. Notably, SRC-2 ablation impairs wheel-running behavior, alters circadian gene expression in several peripheral tissues, alters the rhythmicity of the hepatic metabolome, and deregulates the synchronization of cell-autonomous metabolites. We identify SRC-2 as a potent coregulator of BMAL1:CLOCK and find that SRC-2 targets itself with BMAL1:CLOCK in a feedforward loop. Collectively, our data suggest that SRC-2 is a transcriptional coactivator of the BMAL1:CLOCK oscillators and establish SRC-2 as a critical positive regulator of the mammalian circadian clock.
哺乳动物生物钟的同步是通过以 BMAL1:CLOCK 异二聚体为中心的复杂转录和翻译反馈环实现的。对生物钟反馈环的调节对于维持节律性至关重要，但转录共激活因子在驱动 BMAL1:CLOCK 转录网络中的作用在很大程度上仍未得到探索。在这里，我们显示了昼夜节律性肝甾体受体共激活因子 2（SRC-2）在光周期期间与 BMAL1 顺式作用元件广泛重叠的基因组募集，靶向富含昼夜节律和代谢过程的基因。值得注意的是，SRC-2 的缺失会损害轮跑行为，改变几个外周组织的昼夜节律基因表达，改变肝脏代谢组的节律性，并扰乱细胞自主代谢物的同步性。我们确定 SRC-2 是 BMAL1:CLOCK 的有力共激活因子，并发现 SRC-2 与 BMAL1:CLOCK 以正反馈环的形式靶向自身。总的来说，我们的数据表明 SRC-2 是 BMAL1:CLOCK 振荡器的转录共激活因子，并确立 SRC-2 是哺乳动物生物钟的关键正调控因子。
