Epigenetic Regulation of Adipogenesis

大多数组蛋白甲基转移酶和去甲基化酶是在21世纪世纪发现的，但其生物学功能尚不清楚。我们使用脂肪形成作为一个模型系统来研究组蛋白甲基转移酶和去甲基化酶的作用，以及位点特异性组蛋白甲基化的动力学，在基因表达和细胞分化的调节。我们对组蛋白H3的K4、K9和K27（分别为H3 K4、H3 K9和H3 K27）上的甲基化感兴趣。Polycomb repressive complex 2（PRC 2）是动物发育的主要调节因子。PRC 2主要通过其酶亚基Ezh 2介导的H3 K27（H3 K27 me 3）上的三甲基化来抑制基因表达。使用Ezh 2条件性KO前脂肪细胞，我们报告了Ezh 2及其H3 K27甲基转移酶活性是脂肪生成所需的，并且Ezh 2组成型抑制Wnt基因以促进脂肪生成（Wang L，PNAS 2010）。组蛋白甲基转移酶G9 a负责H3 K9二甲基化（H3 K9 me 2），这是基因阻遏的表观遗传标记。我们最近报道了G9 a抑制PPAR的表达和脂肪形成。G9 a调节脂肪形成的正性和负性主调节因子：G9 a依赖于其H3 K9甲基转移酶活性抑制PPAR表达，同时独立于其酶活性促进Wnt表达（Wang L，EMBO J 2013）。结合我们的报告，H3 K4 me 1/2甲基转移酶MLL 3/MLL 4是PPAR和C/EBP表达和脂肪生成所必需的（Lee JE，eLife 2013），这些发现提供了脂肪生成的表观遗传调控的初步观点，并表明组蛋白甲基化控制脂肪生成的阳性和阴性主调节因子的表达（在BBA 2012和Cell & Biosci 2014中综述）。

The vast majority of histone methyltransferases and demethylases were identified in the 21st century but their biological functions are poorly understood. We use adipogenesis as a model system to study the roles of histone methyltransferases and demethylases, and the dynamics of site-specific histone methylation, in regulation of gene expression and cell differentiation. We are interested in methylations on K4, K9 and K27 of histone H3 (H3K4, H3K9 and H3K27, respectively). The Polycomb repressive complex 2 (PRC2) is a major regulator of animal development. PRC2 represses gene expression mainly through its enzymatic subunit Ezh2-mediated tri-methylation on H3K27 (H3K27me3). Using Ezh2 conditional KO preadipocytes, we report that Ezh2 and its H3K27 methyltransferase activity are required for adipogenesis and that Ezh2 constitutively represses Wnt genes to facilitate adipogenesis (Wang L, PNAS 2010). Histone methyltransferase G9a is responsible for H3K9 di-methylation (H3K9me2), an epigenetic mark for gene repression. Using G9a conditional KO preadipocytes, we report recently that G9a represses PPARγ expression and adipogenesis. G9a regulates both positive and negative master regulators of adipogenesis: G9a represses PPARγ expression dependent on its H3K9 methyltransferase activity while promotes Wnt expression independent of its enzymatic activity (Wang L, EMBO J 2013). Together with our reports that H3K4me1/2 methyltransferases MLL3/MLL4 are required for PPARγ and C/EBPα expression and adipogenesis (Lee JE, eLife 2013), these findings provide an initial view of epigenetic regulation of adipogenesis, and suggest that histone methylations control expression of positive and negative master regulators of adipogenesis (reviewed in BBA 2012 and Cell & Biosci 2014).