KDM4A regulates myogenesis by demethylating H3K9me3 of myogenic regulatory factors

Cell Death Dis. 2021 May 19;12(6):514. doi: 10.1038/s41419-021-03799-1.

Abstract

Histone lysine demethylase 4A (KDM4A) plays a crucial role in regulating cell proliferation, cell differentiation, development and tumorigenesis. However, little is known about the function of KDM4A in muscle development and regeneration. Here, we found that the conditional ablation of KDM4A in skeletal muscle caused impairment of embryonic and postnatal muscle formation. The loss of KDM4A in satellite cells led to defective muscle regeneration and blocked the proliferation and differentiation of satellite cells. Myogenic differentiation and myotube formation in KDM4A-deficient myoblasts were inhibited. Chromatin immunoprecipitation assay revealed that KDM4A promoted myogenesis by removing the histone methylation mark H3K9me3 at MyoD, MyoG and Myf5 locus. Furthermore, inactivation of KDM4A in myoblasts suppressed myoblast differentiation and accelerated H3K9me3 level. Knockdown of KDM4A in vitro reduced myoblast proliferation through enhancing the expression of the cyclin-dependent kinase inhibitor P21 and decreasing the expression of cell cycle regulator Cyclin D1. Together, our findings identify KDM4A as an important regulator for skeletal muscle development and regeneration, orchestrating myogenic cell proliferation and differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Cell Line
  • Cell Proliferation / physiology
  • Histone Demethylases / metabolism*
  • Histones / metabolism
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Development / physiology*
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism
  • Myogenic Regulatory Factors / metabolism*
  • Regeneration / physiology
  • Satellite Cells, Skeletal Muscle / cytology
  • Satellite Cells, Skeletal Muscle / metabolism
  • Stem Cells / cytology
  • Stem Cells / metabolism

Substances

  • Histones
  • Myogenic Regulatory Factors
  • Histone Demethylases
  • JMJD2A protein, mouse
  • Jumonji Domain-Containing Histone Demethylases
  • KDM4A protein, human