G9a-mediated methylation of ERα links the PHF20/MOF histone acetyltransferase complex to hormonal gene expression

The euchromatin histone methyltransferase 2 (also known as 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 coactivator of the endogenous oestrogen receptor alpha (ER alpha) in breast cancer cells in a histone methylation-independent manner. G9a dimethylates ER alpha at K235 both in vitro and in cells. Dimethylation of ER alpha K235 is recognized by the Tudor domain of PHF20, which recruits the MOF histone acetyltransferase (HAT) complex to ER alpha target gene promoters to deposit histone H4K16 acetylation promoting active transcription. Together, our data suggest the molecular mechanism by which G9a functions as an ER alpha coactivator. Along with the PHF20/MOF complex, G9a links the crosstalk between ER alpha methylation and histone acetylation that governs the epigenetic regulation of hormonal gene expression.