G9a-Mediated Methylation of ERα Links the PHF20/MOF Histone Acetyltransferase Complex to Hormonal Gene Expression

The euchromatin histone methyltransferase 2 (EHMT2, aka G9a) methylates histone H3K9 to repress gene expression, but it also acts as a coactivator for some nuclear receptors. The molecular mechanisms underlying this activation remain elusive. Here we show that G9a functions as a bona fide coactivator of the endogenous estrogen receptor α (ERα) in breast cancer cells in a histone methylation-independent manner. G9a dimethylates ERα protein at lysine 235 both in vitro and in cells. Dimethylation of ERαK235 (ERαK235me2) is recognized by the Tudor domain of PHF20, which in turn recruits the MOF histone acetyltransferase (HAT) complex to ERα target gene promoters to deposit histone H4K16 acetylation promoting active transcription. Together, our in vitro and in vivo data establish the molecular mechanism by which G9a functions as an ERα coactivator. Along with the PHF20/MOF complex, G9a links the crosstalk between ERα methylation and histone acetylation governing the epigenetic regulation of hormonal gene expression. G9a KD RNA-seq and PHF20 KD RNA-seq with and without E2 treatment