Per1/Per2–Igf2 axis–mediated circadian regulation of myogenic differentiation |
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| Authors: | Nobuko Katoku-Kikyo Ellen Paatela Daniel L. Houtz Britney Lee Dane Munson Xuerui Wang Mohammed Hussein Jasmeet Bhatia Seunghyun Lim Ce Yuan Yoko Asakura Atsushi Asakura Nobuaki Kikyo |
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| Affiliation: | 1.Stem Cell Institute, University of Minnesota, Minneapolis, MN;2.Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN;3.Bioinformatics and Computational Biology Graduate Program, University of Minnesota, Minneapolis, MN;4.Paul & Sheila Wellstone Muscular Dystrophy Center, University of Minnesota, Minneapolis, MN;5.Department of Neurology, University of Minnesota, Minneapolis, MN |
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| Abstract: | 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. |
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