参与表观遗传调控的代谢小分子群的鉴定及作用机理研究

项目名称： 参与表观遗传调控的代谢小分子群的鉴定及作用机理研究

项目编号： No.31330023

项目类型： 重点项目

立项/批准年度： 2014

项目学科： 生物科学

项目作者： 赵世民

作者单位： 复旦大学

项目金额： 301万元

中文摘要： 我们前期的系列工作表明：a-酮戊二酸、琥珀酸、富马酸等代谢物浓度的改变可以调控细胞表观遗传和信号通路（Science 2009，Cancer Cell 2011），并深刻影响细胞生理病理。因此，在全细胞水平系统鉴定参与表观遗传调控的代谢物并阐明其调控生化机制可以深刻揭示代谢失调导致疾病的分子机理。本项目将利用代谢物与双加氧酶相互作用的原理，在全细胞水平鉴定与组蛋白去甲基化酶和DNA羟甲基化酶相互作用的代谢物，用色-质联用检测技术检测这些代谢物并建立参与细胞表观遗传调控的代谢物库。选择其中的代表性代谢物，研究代谢物分别通过结合非催化位点改变去甲基化酶构象而改变酶活，通过竞争结合底物位点抑制去甲基化酶活，以及通过代谢物修饰改变去甲基化酶活的分子机制。进而，研究影响这些代谢物平衡的上游信号及代谢通路协调，实现通过调控代谢物平衡来实现对细胞表观遗传的调控，加深对代谢物调控表观遗传的分子机制的认识。

中文关键词： 代谢物;相互作用;调控;去甲基化;表观遗传

英文摘要： Our previous results showed that metabolites such as a-ketoglutarate, succinate and fumarate, beside being energy source and building blocks of cells, exert regulatory effects to histone demethylases and DNA demethylases, thus alter epigentics of cells. In this study, we set out a goal to identify metabolites at whole cell level to build a histone and DNA interacting metabolites library, by employing protein-metabolites interaction enrichment technology followed by LC-MS analysis. Mechanistic studies will be carried out for representative metabolites that exert their regulatory effect via binding to allosteric sites of demethylases thus affect demethylases activities, binding to substrates binding sites to competitively inhibit demethylases and to modify demethylases thus alter their activities, respectively. Moreover, we will identify upstream signals and metabolic pathway coordination that determine the level of the regulatory metabolites and try to modulate epigenetics by altering metabolism. Our study will provide value in understanding how metabolism disorders cause human diseases and may provide ways of intervening.

英文关键词： metabolites;interaction;regulation;demethylation;epigenetics