Catalytic Independent Functions of Histone Deacetylase 3 in Metabolism

描述(申请人提供)：第I类组蛋白脱乙酰酶HDAC3是脂肪生成、昼夜节律信号和肝脏新陈代谢的重要表观组学介质，是对抗代谢紊乱(如2型糖尿病)的潜在有用靶点。我们最近发现，HDAC3在肝脂代谢中具有脱乙酰酶不依赖的功能。我推测，HDAC3与尚未被发现的蛋白质复合体一起作为分子平台控制肝脏中的脂质平衡，而不是其酶活性。我的第一个具体目标是研究体内HDAC3对脱乙酰酶非依赖的全基因组转录调控。我们将研究交叉和分化转录图谱、全基因组HDAC3结合和组蛋白修饰的比较，以了解HDAC3在肝脏脂质调节中的作用。我的第二个具体目标将是利用最先进的蛋白质组学工具和分析在体内表征新的含有HDAC3的蛋白质复合体。新的复合体将使用结合缺陷突变体进行研究，并对它们在监督参与脂肪生成的肝脏转录网络中的作用进行获得和丧失功能的研究。这项研究的结果将阐明哺乳动物生物能量学在肝脏中转录调控的基本机制。此外，这项工作可能揭示代谢调节的新机制，可用于开发预防和治疗代谢紊乱的治疗方法。

DESCRIPTION (provided by applicant): The Class I histone deacetylase HDAC3 is an important epigenomic mediator of lipogenesis, circadian signaling, and metabolism in liver, that is a potentially useful therapeutic target to combat metabolic disorders such as Type 2 Diabetes. We have recently discovered that HDAC3 possesses deacetylase- independent functions in hepatic lipid metabolism. I hypothesize that discrete from its enzymatic activity, HDAC3 functions in conjunction with as yet to be discovered protein complexes as a molecular platform to control lipid homeostasis in the liver. My first specific aim is to investigate deacetylase- independent genome-wide transcriptional regulation by HDAC3 in vivo. Comparison of intersecting and divergent transcriptional profiles, genome-wide HDAC3 binding, and histone modifications will be studied to understand the roles of HDAC3 in hepatic lipid regulation. My second specific aim will be to characterize novel HDAC3-containing protein complexes in vivo using state-of-the-art proteomic tools and analyses. New complexes will be investigated using binding-deficient mutants and gain and loss-of function studies for their role in supervising liver transcriptional networks involved in lipogenesis. The results of this study wil elucidate basic mechanisms of transcriptional control of mammalian bioenergetics in the liver. Furthermore, this work may uncover novel mechanisms of metabolic regulation that can be exploited for the development of therapies for the prevention and treatment of metabolic disorders.