Abstract/Summary Most mammalian genes harbor multiple cleavage and polyadenylation sites, or PASs, across the gene body, resulting in mRNA isoforms with different coding sequences (CDS) and/or 3’ untranslated regions (3’UTRs). Alternative cleavage and polyadenylation (APA) is an important layer of gene regulation, affecting gene expression levels, protein diversity, and mRNA metabolism. The APA isoform expression varies across cell types and is dynamically regulated in a growing number of cell conditions, such as cell proliferation and differentiation, change of metabolic states, and cellular stress. Our lab employs interdisciplinary approaches to study APA, involving molecular biology, functional genomics, and computational biology. Our long-term goal is to understand the functional genomics of APA across species as well as molecular mechanisms and cellular consequences of gene regulation by APA in different cell contexts and pathological conditions. In the next five years, we plan to address a few key gaps in the field: First, we plan to examine regulatory rules governing intronic polyadenylation that leads to early termination of transcription. Second, we will examine the role of 3’UTR isoform regulation in cell metabolic reprogramming, such as growth and autophagy. Third, we will investigate the mechanisms and consequences of the unique APA isoform profile in secretory cells.