Histone methyltransferase MLL4 controls myofiber identity and muscle performance through MEF2 interaction

J Clin Invest. 2020 Sep 1;130(9):4710-4725. doi: 10.1172/JCI136155.

Abstract

Skeletal muscle depends on the precise orchestration of contractile and metabolic gene expression programs to direct fiber-type specification and to ensure muscle performance. Exactly how such fiber type-specific patterns of gene expression are established and maintained remains unclear, however. Here, we demonstrate that histone monomethyl transferase MLL4 (KMT2D), an enhancer regulator enriched in slow myofibers, plays a critical role in controlling muscle fiber identity as well as muscle performance. Skeletal muscle-specific ablation of MLL4 in mice resulted in downregulation of the slow oxidative myofiber gene program, decreased numbers of type I myofibers, and diminished mitochondrial respiration, which caused reductions in muscle fatty acid utilization and endurance capacity during exercise. Genome-wide ChIP-Seq and mRNA-Seq analyses revealed that MLL4 directly binds to enhancers and functions as a coactivator of the myocyte enhancer factor 2 (MEF2) to activate transcription of slow oxidative myofiber genes. Importantly, we also found that the MLL4 regulatory circuit is associated with muscle fiber-type remodeling in humans. Thus, our results uncover a pivotal role for MLL4 in specifying structural and metabolic identities of myofibers that govern muscle performance. These findings provide therapeutic opportunities for enhancing muscle fitness to combat a variety of metabolic and muscular diseases.

Keywords: Epigenetics; Metabolism; Muscle Biology; Skeletal muscle; Transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Child
  • Female
  • Gene Expression Regulation*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Humans
  • MEF2 Transcription Factors / genetics
  • MEF2 Transcription Factors / metabolism*
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism*
  • Myofibrils / genetics
  • Myofibrils / metabolism*
  • Oxidative Stress
  • Transcription, Genetic*

Substances

  • MEF2 Transcription Factors
  • Histone-Lysine N-Methyltransferase
  • MLL4 protein, human
  • MLL4 protein, mouse