Regulation of alternative cleavage and polyadenylation

Wistar Institute, Philadelphia PA

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Abstract

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.