赖氨酸琥珀酰化调控组蛋白及DNA甲基化的分子机理

We elucidated that cancerous metabolic enzyme mutations, such as isocitrate dehydrogenase 1 (IDH1) mutations, fumarate hydratase (FH) mutations and succinate dehydrogenase (SDH) mutations, promote hypermethylator phenotypes through accumulating alpha-ketoglutarate structural analogous metabolites that inhibits alpha-ketoglutarate dependent demethylases（Science，2009；Cancer Cell，2011）. We recently found that these metabolic enzyme mutations also cause hypermethylation in histones and DNA through promoting hypersuccinylation, albeit the molecular mechanism remains to be elucidated (Molecular Cell， 2015）.In current study, we will investigate how lysine succinylation that is already known to occur in methylation- and demethylation-related enzymes, such as in histones methylation regulatory proteins LSD1,HMT and JmjC family proteins, DNA methylation regulatory proteins DNMT, TET and TDG, will regulate activities of these enzymes. Moreover, we will look into how lysine succinylation will affect homeostasis of methylation of histones and DNA through alterating equilibrium of methylation and demethylation processes. We will further elucidate the consequences of altered methylation in promoting and maintaining stemness, promoting cell proliferation and inducing tumor-like metabolism. The success of this project may elucidate the underlying mechanism of how deregulated metabolites affect epigenetics and shed lights on potential novel treatments to related cancers.

IDH、FH及SDH等代谢酶的突变通过重编程细胞表观遗传导致肿瘤发生。我们继发现这些突变累积酮戊二酸结构类似物、抑制去甲基化相关双加氧酶导致组蛋白及DNA甲基化升高后（Science，2009；Cancer Cell，2011），近期又发现这些突变还通过诱导蛋白质赖氨酸高琥珀酰化调控相关甲基化水平（Molecular Cell， 2015），揭示了一种新的表观遗传调控机制。为阐明琥珀酰化调控甲基化的分子机理，本项目将以组蛋白甲基化调控蛋白LSD1、HMT和JmjC家族，DNA甲基化调控蛋白DNMT、TET和TDG等为目标，开展琥珀酰化对其调控研究；探讨琥珀酰化如何改变组蛋白及DNA甲基化的稳态平衡；揭示这些代谢酶突变通过诱导高琥珀酰化增进细胞干性、促进细胞增殖及驱使细胞肿瘤样代谢等。项目的实施将阐明代谢酶突变相关高琥珀酰化调控表观遗传的分子机理，为相关肿瘤干预新方法的转化研究提供理论基础。

IDH、FH及SDH等代谢酶的突变通过重编程细胞表观遗传导致肿瘤发生。我们继发现这些突变累积酮戊二酸结构类似物、抑制去甲基化相关双加氧酶导致组蛋白及DNA甲基化升高后（Science，2009；Cancer Cell，2011），近期又发现这些突变还通过诱导蛋白质赖氨酸高琥珀酰化调控相关甲基化水平（Molecular Cell， 2015），揭示了一种新的表观遗传调控机制。为阐明琥珀酰化调控甲基化的分子机理，本项目将以组蛋白甲基化调控蛋白LSD1、HMT和JmjC家族，DNA甲基化调控蛋白DNMT、TET和TDG等为目标，开展琥珀酰化对其调控研究；探讨琥珀酰化如何改变组蛋白及DNA甲基化的稳态平衡；揭示这些代谢酶突变通过诱导高琥珀酰化增进细胞干性、促进细胞增殖及驱使细胞肿瘤样代谢等。本项目不仅探索了代谢酶突变相关的高琥珀酰化修饰对组蛋白功能的调控作用，同时也对其他表观遗传修饰的生理病理功能进行了积极的探索。发现了同型半胱氨酸修饰通过修饰赖氨酸调控蛋白超氧化物歧化酶功能的致病机理。项目的实施有助于阐明代谢酶突变相关高琥珀酰化调控表观遗传的分子机理，为相关肿瘤干预新方法的转化研究提供理论基础。