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)
Institute
National Institute of General Medical Sciences (NIGMS)
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
2008-05-01
Project End
2017-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
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
Zheng, Dinghai; Wang, Ruijia; Ding, Qingbao et al. (2018) Cellular stress alters 3'UTR landscape through alternative polyadenylation and isoform-specific degradation. Nat Commun 9:2268
Wang, Ruijia; Nambiar, Ram; Zheng, Dinghai et al. (2018) PolyA_DB 3 catalogs cleavage and polyadenylation sites identified by deep sequencing in multiple genomes. Nucleic Acids Res 46:D315-D319
Wang, Ruijia; Zheng, Dinghai; Yehia, Ghassan et al. (2018) A compendium of conserved cleavage and polyadenylation events in mammalian genes. Genome Res 28:1427-1441
Fomin, Vitalay; Richard, Patricia; Hoque, Mainul et al. (2018) The C9ORF72 Gene, Implicated in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia, Encodes a Protein That Functions in Control of Endothelin and Glutamate Signaling. Mol Cell Biol 38:
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Zheng, Dinghai; Tian, Bin (2017) Polyadenylation Site-Based Analysis of Transcript Expression by 3'READS. Methods Mol Biol 1648:65-77
Liu, Xiaochuan; Freitas, Jaime; Zheng, Dinghai et al. (2017) Transcription elongation rate has a tissue-specific impact on alternative cleavage and polyadenylation in Drosophila melanogaster. RNA 23:1807-1816
Yurko, Nathan; Liu, Xiaochuan; Yamazaki, Takashi et al. (2017) MPK1/SLT2 Links Multiple Stress Responses with Gene Expression in Budding Yeast by Phosphorylating Tyr1 of the RNAP II CTD. Mol Cell 68:913-925.e3

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