WDR82介导Setd1A复合物定位于基因转录起始位点进而调控基因转录的分子机理研究

WDR82蛋白作为Setd1A/B复合物中重要的调控蛋白在胚胎发育过程中发挥重要作用，其缺失将会导致胚胎发育延迟和胚胎死亡等现象。最新研究表明，WDR82蛋白通过同时识别结合SETD1A蛋白的N端和RNA聚合酶Ⅱ的磷酸化C端结构域介导Setd1A复合物定位于目的基因的转录起始位点，从而调控基因转录。但WDR82介导这一过程的分子结合机理还不清楚。本项目拟在上述研究基础上，解析WDR82-SETD1A-RNA聚合酶Ⅱ的磷酸化C端结构域的复合体结构，并结合多种分子生物学、生物物理学手段，从分子水平揭示WDR82同时结合SETD1A蛋白的N端和RNA聚合酶Ⅱ的磷酸化C端结构域介导Setd1A复合物定位于目的基因转录起始位点的分子机理，阐明WDR82蛋白在Setd1A复合物调控基因转录过程中的重要作用；本项目的顺利实施，将为后续的药物开发提供分子结构和理论基础。

WDR82, as an important regulatory component of Setd1A/B methyltransferase complexes, plays a crucial role in normal early embryonic development. A defect in WDR82 leads to stunted embryonic development and death. Recently, it was demonstrated that WDR82 interacts with the N terminal of SETD1A and additionally binds to the phosphorylated C-terminal domain of RNA polymerase II, which can recruit the Setd1A methyltransferase complex to transcription start sites of transcribed genes. However, the molecular mechanism of WDR82 how to recruit the Setd1A methyltransferase complex to transcription start sites of transcribed genes is still elusive. Hence, this project plans to get the ternary complex structure of WDR82, SETD1A and phosphorylated C-terminal domain of RNA polymerase II, coupled with molecular biological and biophysical experiments to elaborate the molecular mechanism of WDR82 recruiting Setd1A methyltransferase complex to the transcription start sites through interacting with the N terminal of SETD1A and phosphorylated C-terminal domain of RNA polymerase II. Furthermore, we will illustrate the functional significance of WDR82 involved in regulating of Setd1A complex at transcriptionally active genes. Finally, the information derived from these studies will lay an important foundation for further drug discovery.