AFF1和AFF4形成分子开关调控细胞分化

项目名称： AFF1和AFF4形成分子开关调控细胞分化

项目编号： No.31501096

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 生物科学

项目作者： 刘敏

作者单位： 厦门大学

项目金额： 21万元

中文摘要： 新近发现的超级转录延伸因子SECs是细胞内极其重要的蛋白复合体，它参与调控多种生理病理活动，然而目前对SECs如何参与细胞分化的调控仍知之甚少。我们前期的结果提示：SECs的骨架蛋白AFF1和AFF4可能参与3T3L1细胞分化，其内在的分子机理与组蛋白修饰和泛素化信号有关。本项目拟从AFF1和AFF4竞争结合复合体Dot1L/ENL入手，探讨这种竞争性的相互作用如何影响组蛋白的修饰并进而引起分化相关基因的转录活化，以及泛素化信号如何通过调控的蛋白表达水平，驱动AFF1和AFF4形成调控细胞分化的分子开关。期望能通过阐释SECs调控细胞分化的分子机理，为全面了解SECs的生物学功能提供参考，也为挖掘潜在的临床应用价值提供理论依据。

中文关键词： 细胞分化；转录调控；表观遗传；泛素化；超级转录延伸复合体

英文摘要： Although the novel identified super elongation complexes (SECs) are believed to be the key cellular factors to control multiple events under both physiological and pathological conditions, however, it’s still unclear how these complexes are engaged in the regulation of cell differentiation. Our previous data suggest that AFF1 and AFF4, the bridging proteins of SECs, are probably involved in controlling the cell differentiation. The underlying molecular mechanisms are thought to be associated with the histone modification and the ubiquitination. Therefore, we will start from providing the evidences that the regulation of cell differentiation by AFF1 and AFF4 is largely due to the competitive interactions between them with the Dot1L/ENL complex which further affect the histone modification and subsequent transcriptional activation. The ubiquitination signaling forces the operation of molecular switch between AFF1 and AFF4 by changing their expression level to thereby control the cell differentiation. We expect to reveal the above molecular mechanisms that regulate the cell differentiation and further extend the pivotal roles of SECs, and explore their potential for clinical applications.

英文关键词： Cell Differentiation;Transcriptional Regulation;Epigenetics;Ubiquitination;Super Elongation Complexes