Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Science. 2020 Feb 14;367(6479):800-806. doi: 10.1126/science.aaw7365.
Circadian (~24 hour) clocks have a fundamental role in regulating daily physiology. The transcription factor BMAL1 is a principal driver of a molecular clock in mammals. deletion abolishes 24-hour activity patterning, one measure of clock output. We determined whether function is necessary for daily molecular oscillations in skin fibroblasts and liver slices. Unexpectedly, in knockout mice, both tissues exhibited 24-hour oscillations of the transcriptome, proteome, and phosphoproteome over 2 to 3 days in the absence of any exogenous drivers such as daily light or temperature cycles. This demonstrates a competent 24-hour molecular pacemaker in knockouts. We suggest that such oscillations might be underpinned by transcriptional regulation by the recruitment of ETS family transcription factors, and nontranscriptionally by co-opting redox oscillations.
生物钟（约 24 小时）在调节日常生理方面起着重要作用。转录因子 BMAL1 是哺乳动物分子钟的主要驱动因素。缺失会消除 24 小时的活动模式，这是生物钟输出的一个衡量标准。我们确定了 功能是否对皮肤成纤维细胞和肝切片中的日常分子振荡是必要的。出乎意料的是，在 基因敲除小鼠中，在没有任何外源性驱动因素（如每日光照或温度循环）的情况下，两种组织的转录组、蛋白质组和磷酸化蛋白质组在 2 到 3 天内都表现出 24 小时的振荡。这表明 基因敲除小鼠中存在一个功能正常的 24 小时分子起搏器。我们认为，这种振荡可能是通过 ETS 家族转录因子的转录调控，以及通过氧化还原振荡的非转录方式来支撑的。
