表观遗传修饰介导的分子识别互作是真核生物表观遗传调控基因表达和分化、发育等各项生命活动的核心机制之一。申请人最近发现AF9/ENL YEATS结构域是一类新型组蛋白酰基化（如乙酰化、巴豆酰化）识别因子，并招募下游一系列互作分子协同调控基因表达，与炎症反应、白血病发生密切相关。非常有意思的是，AF9/ENL YEATS结构域还可与PAF1相互作用，并与组蛋白修饰识别之间存在着某种竞争关系，但具体作用模式和分子机制尚不清楚。. 本项目拟综合运用结构生物学、生物化学手段，旨在获取AF9/ENL YEATS结构域与PAF1复合物三维结构，从而在原子水平阐明其如何实现与组蛋白修饰识别相互竞争；同时，进一步利用细胞生物学、生物信息学等手段，并结合基于结构的定点突变，深入探讨AF9/ENL YEATS结构域（肿瘤突变体）结构、组蛋白修饰及PAF1复合物三者之间的功能关联和作用机理。

Epigenetic modification-mediated molecular recognition and interaction is central to epigenetic regulation in eukaryotic gene expression, differentiation and development. The applicant recently found that AF9/ENL YEATS domain is a novel family of histone acylation (e.g. acetylation, crotonylation)-binding module and then recruit multiple downstream interactors to regulate gene expression, correlating with inflammatory response and leukemia. Very interestingly, AF9/ENL YEATS domain show potential interaction with PAF1, the RNA Pol II-associated factor 1, imposing competitive effect on histone modification readout. So far, the underlying interaction mode and molecular mechanism remain elusive.. This project aims to get the 3D structure of AF9/ENL YEATS domain in complex with PAF1 via structural and biochemical approaches to elucidate where the competitive binding between PAF1 and histone modification comes from. On the other hand, via cellular and bioinformatics methods as well as structure-guided mutagenesis, we will try to explore the relationship between AF9/ENL YEATS(tumor-related gain-of-function mutants) structure、histone modification and PAF1 complex and underlying mechanisms of their functional significances.