Epigenetic Regulation of Adipogenesis

绝大多数组蛋白甲基转移酶和去甲基化酶是在21世纪发现的，但它们的生物学功能尚不清楚。我们以脂肪形成为模型系统，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中的调节作用。我们对组蛋白H3的K4、K9和K27上的甲基化感兴趣（分别是H3K4、H3K9和H3K27）。Polycomb suppression complex 2 （PRC2）是动物发育的主要调控因子。PRC2主要通过其酶亚基ezh2介导的H3K27上的三甲基化（H3K27me3）抑制基因表达。利用Ezh2条件KO前脂肪细胞，我们报道了Ezh2及其H3K27甲基转移酶活性是脂肪形成所必需的，并且Ezh2组成性地抑制Wnt基因以促进脂肪形成（Wang L, PNAS 2010）。组蛋白甲基转移酶G9a负责H3K9二甲基化（H3K9me2），这是基因抑制的表观遗传标记。使用G9a条件KO前脂肪细胞，我们最近报道G9a抑制PPAR&#947；表达和脂肪形成。G9a调节脂肪形成的正、负主调控因子：G9a通过H3K9甲基转移酶活性抑制PPAR&#947；的表达，而不依赖于其酶活性促进Wnt的表达（Wang L, EMBO J 2013）。加上我们关于H3K4me1/2甲基转移酶MLL3/MLL4是PPAR&#947；和C/EBP&#945；表达和脂肪形成所必需的报告（Lee JE, eLife 2013），这些发现提供了脂肪形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形成的阳性和阴性主调控因子的表达（BBA 2012和Cell & Biosci 2014）。

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).