Regulation of Alternative Cleavage and Polyadenylation

描述(由申请人提供)： 前mRNA裂解/多聚腺苷化(C/P)定义了成熟转录本的3‘端。超过一半的人类基因具有多个C/P位点(PA)，导致了具有不同编码序列(CDS)和/或3‘非翻译区(3’UTRs)的mRNA异构体。选择性PA选择(APA)被认为是基因调控的重要环节，影响蛋白质多样性和mRNA代谢。基因的APA模式在不同的细胞/组织类型中有所不同，并在不同的条件下受到动态调节，如发育和分化。然而，人们对APA的作用机制知之甚少。我们的长期目标是了解APA是如何在细胞/组织类型以及发育和分化过程中受到调控的。在这项资助中，我们有四个特定的目标(SA)：SA-1，利用新转录的RNA分析APA在细胞类型和分化中的调控；SA-2，研究C/P复合体中的RNA结合蛋白如何参与APA；SA-3，研究C/P因子在启动子上的招募如何影响APA；SA-4，研究内含子PA是如何调节的。这项建议旨在建立不同层面的《行政程序法》监管规则。我们期待这项资助的结果将为APA的机制提供系统的观点，并阐明其在细胞功能和分化中的意义。

DESCRIPTION (provided by applicant): Pre-mRNA cleavage/polyadenylation (C/P) defines the 3' end of a mature transcript. Over half of the human genes have multiple C/P sites (pAs), resulting in mRNA isoforms with different coding sequences (CDS) and/or 3' untranslated regions (3'UTRs). Alternative pA selection (APA) is rapidly recognized as an important layer of gene regulation, affecting protein diversity and mRNA metabolism. The APA pattern of genes varies across cell/tissue types and is dynamically regulated under different conditions, such as development and differentiation. The mechanisms of APA, however, are poorly understood. Our long-term goal is to understand how APA is regulated across cell/tissue types and in development and differentiation. In this grant, we have four Specific Aims (SAs): SA-1, to analyze APA regulation across cell types and in differentiation using newly transcribed RNA; SA-2, to examine how RNA-binding proteins in the C/P complex are involved in APA; SA-3, to examine how recruitment of C/P factors at the promoter affects APA; SA-4, to examine how intronic pAs are regulated. This proposal aims to establish rules of APA regulation at different levels. We expect the results of this grant will provide systematic views on the mechanisms of APA and elucidate its significance in cell functions and in differentiation.