Poulard Coralie, Bittencourt Danielle, Wu Dai-Ying, Hu Yixin, Gerke Daniel S, Stallcup Michael R
Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
Department of Biochemistry and Molecular Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA
EMBO Rep. 2017 Aug;18(8):1442-1459. doi: 10.15252/embr.201744060. Epub 2017 Jun 14.
Like many transcription regulators, histone methyltransferases G9a and G9a-like protein (GLP) can act gene-specifically as coregulators, but mechanisms controlling this specificity are mostly unknown. We show that adjacent post-translational methylation and phosphorylation regulate binding of G9a and GLP to heterochromatin protein 1 gamma (HP1γ), formation of a ternary complex with the glucocorticoid receptor (GR) on chromatin, and function of G9a and GLP as coactivators for a subset of GR target genes. HP1γ is recruited by G9a and GLP to GR binding sites associated with genes that require G9a, GLP, and HP1γ for glucocorticoid-stimulated transcription. At the physiological level, G9a and GLP coactivator function is required for glucocorticoid activation of genes that repress cell migration in A549 lung cancer cells. Thus, regulated methylation and phosphorylation serve as a switch controlling G9a and GLP coactivator function, suggesting that this mechanism may be a general paradigm for directing specific transcription factor and coregulator actions on different genes.
与许多转录调节因子一样，组蛋白甲基转移酶G9a和G9a样蛋白（GLP）可作为共调节因子在基因特异性水平发挥作用，但其控制这种特异性的机制大多未知。我们发现，相邻的翻译后甲基化和磷酸化调节G9a和GLP与异染色质蛋白1γ（HP1γ）的结合、与糖皮质激素受体（GR）在染色质上形成三元复合物，以及G9a和GLP作为GR靶基因子集的共激活因子的功能。HP1γ被G9a和GLP招募至与那些糖皮质激素刺激转录需要G9a、GLP和HP1γ的基因相关的GR结合位点。在生理水平上，G9a和GLP的共激活因子功能是A549肺癌细胞中抑制细胞迁移的基因的糖皮质激素激活所必需的。因此，调控的甲基化和磷酸化作为控制G9a和GLP共激活因子功能的开关，这表明该机制可能是指导特定转录因子和共调节因子对不同基因发挥作用的一般模式。
