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

Xi Zhang,Kaori Tanaka,Yuanxin Xi,Wei Li,Danni Peng,Cari A Sagum,Tatiana G Kutateladze,Brianna J Klein,Chao Yuan,Hong Wen,Mark T Bedford,Xiaobing Shi

doi:10.1038/ncomms10810

Abstract

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 α (ERα) in breast cancer cells in a histone methylation-independent manner. G9a dimethylates ERα at K235 both in vitro and in cells. Dimethylation of ERαK235 is recognized by the Tudor domain of PHF20, which recruits the MOF histone acetyltransferase (HAT) complex to ERα target gene promoters to deposit histone H4K16 acetylation promoting active transcription. Together, our data suggest 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 that governs the epigenetic regulation of hormonal gene expression.

Highlights

The euchromatin histone methyltransferase 2 methylates histone H3K9 to repress gene expression, but it acts as a coactivator for some nuclear receptors
G9a has been previously reported to be a coactivator of several nuclear receptors that synergistically cooperate with other nuclear receptor coactivators such as NCOA2, coactivator-associated arginine methyltransferase 1 (CARM1) and p300 to activate transcription in a luciferase-based assay[16]
The E2-induced gene activation was drastically decreased on G9a depletion in T-47D cells (Fig. 1c; Supplementary Fig. 1b), suggesting that G9a is required for the E2-induced expression of the three endogenous oestrogen receptor a (ERa) target genes we tested

Summary

Introduction

The euchromatin histone methyltransferase 2 ( known as G9a) methylates histone H3K9 to repress gene expression, but it acts as a coactivator for some nuclear receptors. Dimethylation of ERaK235 is recognized by the Tudor domain of PHF20, which recruits the MOF histone acetyltransferase (HAT) complex to ERa target gene promoters to deposit histone H4K16 acetylation promoting active transcription. Covalent post-translational modifications (PTMs), such as methylation and acetylation of histones play an essential role in regulating chromatin-associated processes such as transcription[1]. These reversible modifications are catalysed by a number of histone-modifying enzymes. These include histone lysine acetyltransferases (HATs), histone deacetylases, lysine methyltransferases (KMTs) and lysine demethylases, which create a dynamic ‘code’ on histones that serves to recruit ‘reader’ proteins and their associated chromatin regulators. We identified several other enzymes that methylate ERa, including G9a and G9a-like protein (GLP, aka EHMT1)

Methods

Results

Conclusion