N6-methyladenine demethylase ALKBH1 inhibits the differentiation of skeletal muscle

Exp Cell Res. 2021 Mar 15;400(2):112492. doi: 10.1016/j.yexcr.2021.112492. Epub 2021 Jan 30.

Abstract

DNA N6-methyladenine (N6-mA) was recently recognized as a new epigenetic modification in mammalian genome, and ALKBH1 was discovered as its demethylase. Knock-out mice studies revealed that ALKBH1 was indispensable for normal embryonic development. However, the function of ALKBH1 in myogenesis is largely unknown. In this study, we found that N6-mA showed a steady increase, going along with a strong decrease of ALKBH1 during skeletal muscle development. Our results also showed that ALKBH1 enhanced proliferation and inhibited differentiation of C2C12 cells. Genome-wide transcriptome analysis and reporter assays further revealed that ALKBH1 accomplished the differentiation inhibiting function by regulating a core set of genes and multiple signaling pathways, including increasing chemokine (C-X-C motif) ligand 14 (CXCL14) and activating ERK signaling. Taken together, our results demonstrated that ALKBH1 is critical for the myogenic differentiation of C2C12 cells, and suggested that N6-mA might be a new epigenetic mechanism for the regulation of myogenesis.

Keywords: ALKBH1; N(6)-methyladenine; RNA-Seq; Skeletal muscle differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / chemistry
  • AlkB Homolog 1, Histone H2a Dioxygenase / genetics
  • AlkB Homolog 1, Histone H2a Dioxygenase / metabolism*
  • Animals
  • Cell Differentiation*
  • DNA Methylation
  • Epigenesis, Genetic*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle Development*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology*
  • Myoblasts / metabolism
  • Myoblasts / pathology*

Substances

  • AlkB Homolog 1, Histone H2a Dioxygenase
  • Alkbh1 protein, mouse
  • Adenine
  • 6-methyladenine