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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\u2013enhancer 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.<\/jats:p>","DOI":"10.1083\/jcb.202101057","type":"journal-article","created":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T02:23:26Z","timestamp":1619490206000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":49,"title":["Per1\/Per2\u2013Igf2 axis\u2013mediated circadian regulation of myogenic differentiation"],"prefix":"10.1083","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8204-6667","authenticated-orcid":true,"given":"Nobuko","family":"Katoku-Kikyo","sequence":"first","affiliation":[{"name":"Stem Cell Institute, University of Minnesota, Minneapolis, MN 1"},{"name":"Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN 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