报告题目: Transcriptional Elongation and Human Diseases

报告人: 于明，特别研究员，盛毓绶细胞与免疫中心🧑‍🦰，上海交通大学生命科学技术天美。

主持人: 翁杰敏 教授

报告时间: 2016年11月11日13:30

报告地点: 天美娱乐534报告厅

 

报告人简介：于明，2000年获得内蒙古大学天美娱乐微生物学专业学士学位，2005年获得北京大学天美娱乐生物化学与分子生物学专业博士学位🛀，2005年至2007年间在Department of Immunobiology, Yale University School of Medicine 做博士后，2007年至2010年间在Boston Children’s Hospital, Harvard Medical School从事博士后工作，2010年至2016年间在Laboratory of Biochemistry & Molecular Biology, The Rockefeller University从事博士后工作，2016年被聘为上海交通大学生命科学技术天美盛毓绶细胞与免疫中心特别研究员。主要研究方向为血细胞发育和癌症的转录调控。主要利用基因组学技术🤌🏿、分子遗传学技术和蛋白质组学技术来阐明转录调控因子 PAF1 complex、Super Elongation Complex➗、MLL1、GATA1 和 RUNX1 在生理条件下调控血细胞的发育的分子机理以及与它们相关的转录失调诱发癌症的分子机理🫰🏼⏯。

 

报告内容🧜🏼‍♂️：Transcription is the first step of gene expression, in which RNA polymerases use segments of DNA as templates to synthesize RNA. Transcription factor are divers of the development of multi-cellular organisms. They bind DNA and delicately regulate the pre-initiation, initiation, promoter clearance, elongation, and termination stages of transcription. Deregulation of transcription are found in more than 70% of the human cancer cases. Promoter-proximal pausing release of Pol II is an early step of transcriptional elongation and a critical step for transcriptional control in animal cells. The AFF1, AFF4, AF9, and ENL subunits of the P-TEFb and ELL1/2/3-containing super elongation complex (SEC), are also major fusion partners of MLL1 in mixed lineage leukemia (MLL). Yet, their roles in transcriptional regulation and molecular mechanisms underlying the corresponding MLL fusion proteins-mediated persistent gene activation remain unclear. Although the SEC subunits are generally considered positive elongation factors, we found that while AFF4 and ENL play positive roles in promoter-proximal pausing release of RNA polymerase II (Pol II), their AFF1 and AF9 counterparts can actually play negative roles in Pol II pausing release and CTD serine-2 phosphorylation, respectively. In addition, MLL-AF9 may effect persistent gene activation by altering the chromatin occupancy of factors interacting with its AF9 fragment. We also found that the H3K79 methyltransferase DOT1L, which functions in association with AF9 (or MLL-AF9), stabilizes Pol II occupancy on chromatin. Altogether these results provide insights into roles of the SEC and DOT1L in transcriptional regulation as well as molecular mechanisms of MLL fusion proteins mediated persistent gene activation.