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.

Public Health Relevance

Over half of the human genes have multiple cleavage and polyadenylation 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 differs across cell/tissue types and is dynamically regulated under different conditions, such as development and differentiation. The mechanisms of APA, however, are poorly understood. Here we plan to take systematic approaches to examine how APA is regulated across cell types and in differentiation.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM084089-08
Application #
8656128
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Bender, Michael T
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Rutgers University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Newark
State
NJ
Country
United States
Zip Code
07103
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Neve, Jonathan; Burger, Kaspar; Li, Wencheng et al. (2016) Subcellular RNA profiling links splicing and nuclear DICER1 to alternative cleavage and polyadenylation. Genome Res 26:24-35
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Yang, Yan; Li, Wencheng; Hoque, Mainul et al. (2016) Correction: PAF Complex Plays Novel Subunit-Specific Roles in Alternative Cleavage and Polyadenylation. PLoS Genet 12:e1005883
Lemay, Jean-François; Marguerat, Samuel; Larochelle, Marc et al. (2016) The Nrd1-like protein Seb1 coordinates cotranscriptional 3' end processing and polyadenylation site selection. Genes Dev 30:1558-72
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Hu, Wenyan; Li, Shengguo; Park, Ji Yeon et al. (2016) Dynamic landscape of alternative polyadenylation during retinal development. Cell Mol Life Sci :

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