Stem Cell Institute, University of Minnesota, Minneapolis, MN.
Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN.
J Cell Biol. 2021 Jul 5;220(7). doi: 10.1083/jcb.202101057. Epub 2021 May 19.
Circadian rhythms regulate cell proliferation and differentiation, but circadian control of tissue regeneration remains elusive at the molecular level. Here, we show that proper myoblast differentiation and muscle regeneration are regulated by the circadian master regulators Per1 and Per2. Depletion of Per1 or Per2 suppressed myoblast differentiation in vitro and muscle regeneration in vivo, demonstrating their nonredundant functions. Both Per1 and Per2 were required for the activation of Igf2, an autocrine promoter of myoblast differentiation, accompanied by Per-dependent recruitment of RNA polymerase II, dynamic histone modifications at the Igf2 promoter and enhancer, and the promoter-enhancer interaction. This circadian epigenetic priming created a preferred time window for initiating myoblast differentiation. Consistently, muscle regeneration was faster if initiated at night, when Per1, Per2, and Igf2 were highly expressed compared with morning. This study reveals the circadian timing as a significant factor for effective muscle cell differentiation and regeneration.
昼夜节律调节细胞增殖和分化，但昼夜节律对组织再生的分子调控仍难以捉摸。在这里，我们表明，适当的成肌细胞分化和肌肉再生受到昼夜节律主调控因子 Per1 和 Per2 的调节。Per1 或 Per2 的耗竭抑制了体外成肌细胞分化和体内肌肉再生，证明了它们的非冗余功能。Per1 和 Per2 都需要激活 Igf2，这是成肌细胞分化的自分泌启动子，伴随着 Per 依赖性 RNA 聚合酶 II 的募集、Igf2 启动子和增强子的动态组蛋白修饰以及启动子-增强子相互作用。这种昼夜节律表观遗传启动为开始成肌细胞分化创造了一个首选的时间窗口。一致地，如果在夜间开始，即与早晨相比，Per1、Per2 和 Igf2 高度表达时，肌肉再生会更快。这项研究揭示了昼夜节律时间作为有效肌肉细胞分化和再生的重要因素。
