申请人的主要研究领域为基因表达调控与表观遗传学。在基因转录的表观遗传学调控分子机制及其在癌症中的应用研究方面取得了创新性成果。主要包括：发现组蛋白H4K20的去甲基化酶并阐述其在细胞周期调控中的作用及分子机制；发现去甲基化酶远程调控基因转录的新颖模式，提出并定义“抗停顿增强子”；发现组蛋白去甲基化酶的组蛋白和RNA双重酶活性；阐述核受体RXRa致癌分子机制，并发现其为抗炎药舒林酸的作用靶点；优化并合成了抗癌小分子（舒林酸类似物）并进入临床前试验阶段。近5年来以通讯作者/第一作者发表多篇高水平论文，其中包含1篇Cell，1篇Nature，1篇Cancer Cell。论文他引超过1100次。获得两项美国专利。抗癌小分子K-80003在国际上被上百家媒体报道。获得美国加州大学研究基金奖和Susan Komen博士后奖学金，入选中组部“青年千人计划”和福建省“闽江学者”特聘教授等奖励和荣誉。

My research mainly focuses on epigenetic regulation of gene expression. In the past ten years, I have made significant progress and contributions to the understanding of molecular mechanisms underlying epigenetic regulation of gene expression and splicing, and its implication in cancer and other human diseases, which include but not limited to i) Identify the first histone H4 lysine 20 demethylase PHF8 and describe its role in cell cycle regulation and the underlying molecular mechanisms; ii) Reveal a novel paradigm in gene transcription regulation, in which histone demethylase JMJD6 in conjunction with its functional partner Brd4 regulates promoter-proximal Pol II pause release through association with distal enhancers, which we defined as “Anti-pause Enhancers”. The pause release function of JMJD6/Brd4 was primarily achieved through JMJD6 dual enzymatic activities targeting both histone and RNA methylation; iii) Elucidate the molecular mechanisms underlying nuclear receptor RXRa function in promoting cancer cell growth; iv) Identify one of the non-steroid anti-inflammatory drugs, Sulindac, binds to RXRa and inhibits RXRa–mediated cancer cell growth; v) Discover a small molecule, which we named as K-80003, with superior efficacy in inhibiting cancer cell growth, but low toxicity to normal cells in cultured cells, animal models and preclinical studies. The aforementioned research findings along with others have been published in several scientific journals with high impact factors, such as Cell, Nature, Cancer Cell, Molecular Cell and PNAS, among which I am the co-corresponding and first author of one Cell paper, first author of one Nature paper, and co-first author of one Cancer Cell paper. The significance and novelty of my research papers can be seen from the total number of citation received, which is as high as 1,100 times according to SCI database, not counting the Cell paper we recently published. In addition, some of the critical components of our research findings were granted two patents in US. Particularly, anti-cancer small molecule K-80003 has received intensive attention and been reported by major media around the world, including but not limited to CBS News, ABC10 in US, as well as Science and Technology Daily, Xinhua Daily, China Education and Research Network, Ministry of Education, Science and Technology Development Center in China. I was awarded “HUANG MEM SC FND” fellowship for consecutive two years in 2005 and 2006, “Susan G. Komen for the Cure Breast Cancer” Postdoctoral Fellowship in 2012, “One Thousand Young Talents Program” and “Min-Jiang Scholar” distinguished professor in 2013.

本项目集中研究表观遗传调控子（主要为组蛋白甲基转移酶和去甲基化酶）和转录因子在基因表达和可变剪接中的调控分子机制及其潜在应用。在该项目的支持下，项目组揭示了组蛋白去甲基化酶JMJD6是调节雌激素和雌激素受体诱导的增强子RNA产生，邻近编码基因的转录激活和乳腺癌细胞生长和肿瘤形成的重要调节因子，并且这些功能和JMJD6的酶活性密切相关，表明JMJD6是可用于治疗雌激素受体阳性乳腺癌的潜在药物靶点(Molecular Cell,第二轮审稿阶段)；发现JMJD6能直接与RNA结合，并和可变剪接因子U2AF65协同作用，广泛调节基因可变剪接事件，揭示了JMJD6参与疾病特别是癌症发生发展的一个新颖机制 (Nucleic Acid Research,2016 );发现了组蛋白精氨酸甲基转移酶CARM1能够甲基化热休克蛋白HSP70，并且该甲基化对于HSP70参与基因转录调控至关重要 (PNAS,2015);揭示了组蛋白赖氨酸甲基转移酶SET7/9和去甲基化酶LSD1对转录因子YY1及其同源蛋白YY2甲基化修饰的动态调控作用，及其阐述甲基化对于这两个重要的转录因子的DNA结合活性，其参与的基因转录调控，细胞周期调控和肿瘤形成至关重要(Scientific Reports ,2016;Cell Discovery,2017)；发现转录因子TP53是P-TEFb复合体的重要成员之一，通过与增强子结合，调控增强子RNA的产生和邻近相关基因的转录，从而参与癌症发生发展（文章整理投稿中）；另外，我们参与了其它多项关于基因转录调控的研究工作 （Molecular Cell,2015；Molecular Cell,2018）。在成果转化方面，项目负责人参与发现的抗癌小分子TX-803于2016年底获得了美国FDA关于其在晚期结直肠癌中开展临床研究的批件。在获奖方面，项目负责人获得了第八届中国药学会-赛诺菲青年生物药物奖（2016）以及福建省第二十四届运盛青年科技奖（2017）。