Per1/per2–igf2 axis–mediated circadian regulation of myogenic differentiation

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

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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, andIgf2 were highly expressed compared with morning. This study reveals the circadian timing as a significant factor for effective muscle cell differentiation and regeneration.

Original languageEnglish (US)
Article numbere202101057
JournalJournal of Cell Biology
Volume220
Issue number7
DOIs
StatePublished - Jul 5 2021

Bibliographical note

Funding Information:
S. Lim and C. Yuan were supported by the Minnesota Stem Cell Institute. A. Asakura was supported by the National Institutes of Health (R01AR062142 and R21AR070319). N. Kikyo was supported by the National Institutes of Health (R01GM137603 and R21AR076167), Regenerative Medicine Minnesota (RMM 101617 DS 004), and a University of Minnesota grant-in-aid of research (291987). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no competing financial interests.

Funding Information:
We thank James Staats, Brian Ruis, and Allison Keith for technical support; Toshio Kitamura (The Institute of Medical Science, The University of Tokyo, Tokyo, Japan) for the pMXs-IP plasmid and the PLAT-E cells; and Karyn A. Esser for critical reading of the manuscript. We acknowledge the Minnesota Supercomputing Institute, University of Minnesota Informatics Institute, and University of Minnesota Genomics Center for providing high-performance computing resources and the gopher pipelines. S. Lim and C. Yuan were supported by the Minnesota Stem Cell Institute. A. Asakura was supported by the National Institutes of Health (R01AR062142 and R21AR070319). N. Kikyo was supported by the National Institutes of Health (R01GM137603 and R21AR076167), Regenerative Medicine Minnesota (RMM 101617 DS 004), and a University of Minnesota grant-in-aid of research (291987).

Publisher Copyright:
© 2021 Katoku-Kikyo et al.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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