题目: Concentration-dependent regulation of alternative splicing: Roles in differentiation and disease

报告人: James Manley教授

时间:2019年5月13日14:00

地点:教一楼201室

报告人介绍: James Manley博士是美国哥伦比亚大学讲座教授、美国科学院院士、美国科学院生物化学部主任、国际搁狈础生物学领域权威学者,在Cell、 Nature、Science 发表几十篇论文.目前担任Molecular Cell, eLife, Genes & Development等刊物的编委。

报告摘要：

    The concept that changes in alternative splicing patterns can be dictated by changes in the intracellular concentrations of RNA binding proteins (RBPs) is now well documented. One of the very first examples of this was shown over a quarter century ago with the discovery of the first SR protein, SRSF1. SRSF1 was co-discovered in my lab, and was called simply ASF (Alternative Splicing Factor). Since then numerous studies have established the ability of many RBPs that function in regulation of alternative splicing to bring about changes in splicing by concentration-dependent mechanisms. This principal, which is important in alternative mRNA polyadenylation as well as alternative splicing, has been established both with individual target transcripts as well as globally by genome-wide RNA sequencing.

       This mechanism of gene control contributes to numerous important cellular processes, such as cellular differentiation, and also contributes to disease when dysregulated. For example a number of RBPs, including SR proteins and hnRNPs, are overexpressed in cancer, and the resulting splicing changes can contribute to disease progression. Concentration of RBPs can also be altered by sequestration or aggregation. This can involve for example binding to repeat-containing RNAs that arise from nucleotide expansions that characterize a number of neurodegenerative and related diseases.

    I will discuss ongoing work in my lab that addresses all of the above examples. This includes our studies showing how regulated changes in the expression of specific RBPs can play a role in controlling human embryonic stem cell pluripotency, how dysregulation of RBP expression can disrupt alternative splicing in glioblastoma, and how sequestration/aggregation of RBPs can disrupt splicing and contribute to neurodegenerative diseases such as Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.