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Epigenetic Regulation of Adipogenesis

脂肪生成的表观遗传调控

基本信息

批准号：
8939685
负责人：
Kai Ge
金额：
$ 58万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8939685
关键词：
Acetylation Animals Biological Models Biological Process CCAAT-Enhancer-Binding Proteins Cell Differentiation process Cells Complex Development Disease Epigenetic Process Fatty acid glycerol esters G9a histone methyltransferase Gene Activation Gene Expression Gene Expression Regulation Generations Genes Histone Acetylation Histone H3 Histones Ligands Lipodystrophy Lysine Mediating Methylation Methyltransferase Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Obesity PPAR gamma Peroxisome Proliferator-Activated Receptors Play Polycomb Regulation Reporting Role Signal Transduction Site activating transcription factor beta catenin gene repression histone acetyltransferase histone methyltransferase histone modification interest lipid biosynthesis member methylcobalamin-coenzyme M methyltransferase transcription factor

项目摘要

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).

绝大多数组蛋白甲基转移酶和去甲基化酶是在 21 世纪被鉴定出来的，但它们的生物学功能却知之甚少。我们使用脂肪形成作为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态，在基因表达和细胞分化的调节中。我们对组蛋白 H3 的 K4、K9 和 K27（分别为 H3K4、H3K9 和 H3K27）上的甲基化感兴趣。 Polycomb 抑制复合物 2 (PRC2) 是动物发育的主要调节因子。 PRC2 主要通过其酶亚基 Ezh2 介导的 H3K27 (H3K27me3) 三甲基化来抑制基因表达。使用 Ezh2 条件 KO 前脂肪细胞，我们报告 Ezh2 及其 H3K27 甲基转移酶活性是脂肪生成所必需的，并且 Ezh2 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 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，我们最近报告 G9a 抑制 PPARγ 表达和脂肪生成。 G9a 调节脂肪生成的正向和负向主调节因子：G9a 依赖于其 H3K9 甲基转移酶活性来抑制 PPARγ 表达，同时促进 Wnt 表达，而不依赖于其酶活性 (Wang L, EMBO J 2013)。结合我们的报告，H3K4me1/2 甲基转移酶 MLL3/MLL4 是 PPARγ 和 C/EBPα 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正负主调节因子的表达（在 BBA 2012 和 Cell & Biosci 中综述） 2014）。