PHF2 regulates grip strength via demethylation at the promoter region of the Mef2c.

Epigenetic modifications, including DNA methylation and histone modifications, play crucial roles in gene expression. Although histone H3 lysine-9 methylation (H3K9me) is a highly conserved repressive mark in heterochromatin regions, its specific function in skeletal muscle remains unclear. Here we demonstrate that PHF2, an H3K9me2 demethylase, is essential for skeletal muscle function, particularly in fast-twitch muscle fibers. Skeletal muscle-specific Phf2 knockout mice exhibited significantly reduced grip strength compared to controls. PHF2 differentially regulates protein metabolism and energy homeostasis between fast- and slow-twitch fibers, with more pronounced effects in fast-twitch muscles. Moreover, we found that PHF2 predominantly binds to transcription start site (TSS)-downstream regions of key genes, including Mef2c, which play a critical role in muscle function. Notably, PHF2 binding sites were enriched in pathways associated with protein regulation, cellular homeostasis, and muscle function. These findings reveal PHF2's broader regulatory role in maintaining muscle health and performance.