Regulation of alternative cleavage and polyadenylation

项目摘要 大多数哺乳动物基因具有多个切割和多聚腺苷酸化位点，或PAS，导致mRNA 具有不同编码序列（CDS）和/或3'非翻译区（3' UTR）的同种型。替代 切割和多聚腺苷酸化（阿帕）被迅速认为是基因调控的重要层，影响 基因表达、蛋白质多样性和mRNA代谢。基因的阿帕模式在不同的 细胞/组织类型，在增殖、分化和发育中受到动态调节，并改变细胞/组织类型。 对细胞外信号的反应然而，阿帕的机制知之甚少。我们的长期 目的是了解阿帕在生理和生理条件下不同细胞/组织中的“调控代码”， 病理条件。在这一建议中，我们有三个具体目标：第一，我们将系统地研究一个 阿帕法规中的一组终止因素。第二，我们将研究3'端之间的相互作用 加工和剪接在阿帕调节中的作用。第三，我们将开发一种基因组方法来改变阿帕。我们 我希望这项赠款的结果将提供对阿帕机制的全面理解， 通过阿帕调节基因表达的工具。

PROJECT SUMMARY Most mammalian genes harbor multiple cleavage and polyadenylation sites, or PASs, resulting in mRNA isoforms with different coding sequences (CDS) and/or 3’ untranslated regions (3’UTRs). Alternative cleavage and polyadenylation (APA) is rapidly recognized as an important layer of gene regulation, affecting gene expression, protein diversity and mRNA metabolism. The APA pattern of genes varies across cell/tissue types, is dynamically regulated in proliferation, differentiation and development, and alters in response to extracellular cues. The mechanisms of APA, however, are poorly understood. Our long-term goal is to understand the ‘regulatory code’ of APA in different cells/tissues under physiological and pathological conditions. In this proposal, we have three specific aims: First, we will systematically examine a set of termination factors in APA regulation. Second, we will examine the interplay between 3’ end processing and splicing in APA regulation. Third, we will develop a genomic method to alter APA. We expect that the result of this grant will provide comprehensive understanding of the mechanisms of APA and tools to regulate gene expression through APA.