Epigenetic regulation of myogenic gene expression by heterochromatin protein 1 alpha

Heterochromatin protein 1 (HP1) is an essential heterochromatin-associated protein typically involved in the epigenetic regulation of gene silencing. However, recent reports have demonstrated that HP1 can also activate gene expression in certain contexts including differentiation. To explore the role of each of the three mammalian HP1 family members (a, v and g) in skeletal muscle, their expression was individually disrupted in differentiating skeletal myocytes. Among the three isoforms of HP1, HP1a was specifically required for myogenic gene expression in myoblasts only. Knockdown of HP1a led to a defect in transcription of skeletal muscle-specific genes including Lbx1, MyoD and myogenin. HP1a binds to the genomic region of myogenic genes and depletion of HP1a results in a paradoxical increase in histone H3 lysine 9 trimethylation (H3K9me3) at these sites. JHDM3A, a H3K9 demethylase also binds to myogenic gene's genomic regions in myoblasts in a HP1a-dependent manner. JHDM3A interacts with HP1a and knockdown of JHDM3A in myoblasts recapitulates the decreased myogenic gene transcription seen with HP1a depletion. These results propose a novel mechanism for HP1a-dependent gene activation by interacting with the demethylase JHDM3A and that HP1a is required for maintenance of myogenic gene expression in myoblasts.