G9a 作为一个分子支架,将转录共激活因子组装到糖皮质激素受体靶基因的亚类上。
G9a functions as a molecular scaffold for assembly of transcriptional coactivators on a subset of glucocorticoid receptor target genes.
机构信息
Department of Biochemistry and Molecular Biology, USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
出版信息
Proc Natl Acad Sci U S A. 2012 Nov 27;109(48):19673-8. doi: 10.1073/pnas.1211803109. Epub 2012 Nov 14.
Histone H3 lysine-9 methyltransferase G9a/EHMT2/KMT1C is a key corepressor of gene expression. However, activation of a limited number of genes by G9a (independent of its catalytic activity) has also been observed, although the precise molecular mechanisms are unknown. By using RNAi in combination with gene expression microarray analysis, we found that G9a functions as a positive and a negative transcriptional coregulator for discrete subsets of genes that are regulated by the hormone-activated Glucocorticoid Receptor (GR). G9a was recruited to GR-binding sites (but not to the gene body) of its target genes and interacted with GR, suggesting recruitment of G9a by GR. In contrast to its corepressor function, positive regulation of gene expression by G9a involved G9a-mediated enhanced recruitment of coactivators CARM1 and p300 to GR target genes. Further supporting a role for G9a as a molecular scaffold for its coactivator function, the G9a-specific methyltransferase inhibitor UNC0646 did not affect G9a coactivator function but selectively decreased G9a corepressor function for endogenous target genes. Overall, G9a functioned as a coactivator for hormone-activated genes and as a corepressor in support of hormone-induced gene repression, suggesting that the positive or negative actions of G9a are determined by the gene-specific regulatory environment and chromatin architecture. These findings indicate distinct mechanisms of G9a coactivator vs. corepressor functions in transcriptional regulation and provide insight into the molecular mechanisms of G9a coactivator function. Our results also suggest a physiological role of G9a in fine tuning the set of genes that respond to glucocorticoids.
组蛋白 H3 赖氨酸-9 甲基转移酶 G9a/EHMT2/KMT1C 是基因表达的关键核心抑制因子。然而,也观察到 G9a(不依赖其催化活性)可以激活有限数量的基因,尽管确切的分子机制尚不清楚。通过使用 RNAi 结合基因表达微阵列分析,我们发现 G9a 作为激素激活的糖皮质激素受体 (GR) 调控的离散基因子集的正转录和负转录共调节因子发挥作用。G9a 被招募到其靶基因的 GR 结合位点(而不是基因体),并与 GR 相互作用,表明 GR 招募 G9a。与它的共抑制因子功能相反,G9a 对基因表达的正调控涉及 G9a 介导的共激活因子 CARM1 和 p300 对 GR 靶基因的增强募集。进一步支持 G9a 作为其共激活因子功能的分子支架的作用,G9a 特异性甲基转移酶抑制剂 UNC0646 不影响 G9a 共激活因子功能,但选择性地降低内源性靶基因的 G9a 共抑制因子功能。总的来说,G9a 作为激素激活基因的共激活因子和支持激素诱导基因抑制的共抑制因子发挥作用,这表明 G9a 的正或负作用取决于基因特异性调控环境和染色质结构。这些发现表明 G9a 共激活因子与转录调控中的核心抑制因子功能具有不同的机制,并为 G9a 共激活因子功能的分子机制提供了深入的了解。我们的研究结果还表明 G9a 在精细调节对糖皮质激素有反应的基因集合方面具有生理作用。