Research Summary: The role of euchromatic histone-lysine N-methyltransferase 2 (EHMT2/G9a) in skeletal muscle repair and regeneration.
Skeletal muscle regeneration involves complex coordination of satellite cells. An as yet uncharacterized histone mark in myogenesis is dimethylation of the 9th lysine residue on the tail of histone 3 (H3K9me2), produced by euchromatic histone-lysine N-methyltransferase 2 (EHMT2), also known as G9a. However, EHMT2 can also methylate non-histone proteins, direct de novo DNA methylation through interaction with DNA methyltransferases (DNMT), or positively regulate gene expression via a separate transcriptional activation domain. In order to characterize its role in myogenesis, we have generated a floxed allele of EHMT2 in mouse, which we bred to a strain expressing CRE-ERT2 under the control of the Pax7 promoter, allowing the inducible in vivo deletion of EHMT2 in adult satellite cells. When limb muscle was subjected to a dose of snake venom damage in these mice, we observed a catastrophic failure of regeneration. Based on these preliminary data hypothesize that EHMT2 plays a role in myogenic cell maintenance, proliferation or differentiation. Further mechanistic studies are aimed at defining the roles of each domain function at each stage of the myogenic program, through analyses of H3K9me2, DNA methylation, the transcriptome, and EHMT2’s interactions with relevant proteins and DNA loci.