Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. 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 three 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. 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 #
2R01GM084089-06
Application #
8513569
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Bender, Michael T
Project Start
2008-05-01
Project End
2013-06-30
Budget Start
2013-05-01
Budget End
2013-06-30
Support Year
6
Fiscal Year
2013
Total Cost
$51,631
Indirect Cost
$18,211
Name
University of Medicine & Dentistry of NJ
Department
Biochemistry
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Zheng, Dinghai; Tian, Bin (2014) Sizing up the poly(A) tail: insights from deep sequencing. Trends Biochem Sci 39:255-7
Di Giammartino, Dafne Campigli; Li, Wencheng; Ogami, Koichi et al. (2014) RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3' UTRs. Genes Dev 28:2248-60
Kurosaki, Tatsuaki; Li, Wencheng; Hoque, Mainul et al. (2014) A post-translational regulatory switch on UPF1 controls targeted mRNA degradation. Genes Dev 28:1900-16
Hoque, Mainul; Li, Wencheng; Tian, Bin (2014) Accurate mapping of cleavage and polyadenylation sites by 3' region extraction and deep sequencing. Methods Mol Biol 1125:119-29
Rosonina, Emanuel; Yurko, Nathan; Li, Wencheng et al. (2014) Threonine-4 of the budding yeast RNAP II CTD couples transcription with Htz1-mediated chromatin remodeling. Proc Natl Acad Sci U S A 111:11924-31
Hoque, Mainul; Ji, Zhe; Zheng, Dinghai et al. (2013) Analysis of alternative cleavage and polyadenylation by 3' region extraction and deep sequencing. Nat Methods 10:133-9
Elbarbary, Reyad A; Li, Wencheng; Tian, Bin et al. (2013) STAU1 binding 3' UTR IRAlus complements nuclear retention to protect cells from PKR-mediated translational shutdown. Genes Dev 27:1495-510
Luo, Wenting; Ji, Zhe; Pan, Zhenhua et al. (2013) The conserved intronic cleavage and polyadenylation site of CstF-77 gene imparts control of 3' end processing activity through feedback autoregulation and by U1 snRNP. PLoS Genet 9:e1003613
Devany, Emral; Zhang, Xiaokan; Park, Ji Yeon et al. (2013) Positive and negative feedback loops in the p53 and mRNA 3' processing pathways. Proc Natl Acad Sci U S A 110:3351-6
Tian, Bin; Manley, James L (2013) Alternative cleavage and polyadenylation: the long and short of it. Trends Biochem Sci 38:312-20

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