申请人独立工作以来一直从事表观遗传调控蛋白的结构与功能研究，围绕DNA甲基化和组蛋白甲基化修饰关键蛋白的催化、底物识别和酶活调节机制开展了系统性研究。1.DNA甲基化修饰：阐明了TET2识别并氧化甲基化DNA的分子机制；揭示了UHRF1识别组蛋白甲基化以指导DNA甲基化维持，及UHRF1蛋白水平随细胞周期动态变化的机制。2.组蛋白甲基化修饰：阐明了以KDM7A和LSD2为代表的两类组蛋白去甲基化酶的底物识别及酶活调节机制，提出KDM7A与核小体底物“反式结合”模式；发现LSD2存在“双底物识别位点”并阐明NPAC蛋白激活LSD2酶活性的机制。申请人从结构生物学的角度推动了对表观遗传调控机制的深入理解，为学科发展做出了一定贡献，为靶向药物设计奠定了基础。近五年申请人在Cell，Mol Cell，PNAS，Cell Res，JBC等杂志发表通讯作者论文16篇，总影响因子136，他引133次。

The applicant’s research mainly focuses on structural and functional studies of epigenetic regulators. The systematic studies reveal the underlying mechanism of catalysis, substrate recognition and regulation of enzymatic activity of these critical epigenetic regulators, including histone demethylase, DNA methyltransferases, and DNA dioxygenase..DNA methylation is one of the most important epigenetic regulations. The applicant determined the crystal structure of TET2 in complex with methylated DNA and reveal the molecular mechanism of substrate recognition and catalysis of TET proteins. Structural and biochemical analyses of PHD-H3 complex indicate that PHD domain of UHRF1 specifically recognizes unmodified R2 of histone H3, and H3R2 methylation affects UHRF1 mediated gene regulation. The applicant further demonstrated that both TTD and PHD domains are essential for H3K9me3 recognition by UHRF1, and thus reveal the mechanism of UHRF1 mediated histone recognition, which is important for the maintainence of DNA methylation. Biochemical and cellular studies further indicate that USP7 stabilize UHRF1 through interaction with UHRF1, and UHRF1 is degraded in M phase because UHRF1 is phosphorylated by CDK1 and thus lose the interaction with USP7. .Studies of histone demethylase indicate that KDM7A adopts a “trans-binding” mode, with PHD and JmjC domains associate with H3K4me3 and H3k9me2 from two separate histone H3 modules. Studies of LSD2, another type of histone demethylase, reveal that “second substrate binding site” is important for substrate recognition and enzymatic activity of LSD2. We also found NPAC, a LSD2 binding protein, stimulates LSD2 enzymatic activity through residue F217 of NPAC to stabilize the interaction between LSD2 and its substrate. .The above results were published in leading journals, including Cell, Mol Cell, PNAS, Cell Research and JBC. In the past five years, the applicant published 16 corresponding-author papers (Total IF=136), which were cited 133 times.