本项目属于“生物大分子动态修饰的调控机制与功能解析”。针对DNA甲基化修饰对表观遗传调控机制以及小分子对表观遗传干预，我们拟采用毛细管电泳-SELEX技术（指数富集的配体系统进化）和亲和纯化-质谱分析技术，在全蛋白组层面实现高通量、无差异化鉴定甲基化DNA的阅读器。用生物信息学分析，结合分子生物学和生物化学方法解析这些蛋白的功能，揭示DNA甲基化介导的表观遗传的调控机制，阐明表观遗传在人类发育和相关疾病发生中的科学问题。此外,针对具有重要临床意义的甲基化DNA-蛋白质相互作用，采用非平衡毛细管电泳技术，从天然产物和组合化学构建的化合物库中筛选能够调控甲基化DNA介导的表观遗传过程的小分子化合物。研究它们的作用机理，确定构效关系，优化活性，进行抗肿瘤活性研究。 本项目从分子水平研究揭示表观遗传学的机制，并且通过小分子化合物精确调控表观遗传过程，发现治疗肿瘤的新途径。

This project belongs to "Reveal the Regulation Mechanism and Function of Dynamic Modification of Biological Macromolecules". To reveal the mechanism of DNA methylation modification on epigenetic regulation and the intervention of small molecules on epigenetic, we plan to use capillary electrophoresis-SELEX technology (system evolution of ligands by exponentially enriched) and affinity purification-mass spectrometry to realize the high-throughput and unbiased identification of the methylation DNA readers at whole proteome scale. Bioinformatics analysis, combined with molecular biology and biochemical methods will be used to reveal the functions of these proteins, reveal the DNA methylation mediated regulatory mechanism of epigenetics, and clarify the scientific question about epigenetics in human development and related diseases. Furthermore, we will screen the small molecules which can modulate the clinically important methylated DNA-mediated epigenetic process by using non-equilibrium capillary electrophoresis from the compound libraries constructed by natural products and combinatorial chemistry that can regulate the. Study their mechanism of action, determine structure-activity relationship, optimize activity, and conduct anti-tumor activity studies. This project will reveal the mechanism of epigenetics at the molecular level, and discovers new ways to treat tumors through the precise regulation of epigenetic processes by small molecular compounds.