mRNA polyadenylation is an essential step for the maturation of almost all eukaryotic mRNAs. Altered polyadenylation activity caused by genetic mutation has been implicated in a growing number of human diseases. Over half of the human genes contain multiple polyadenylation sites [poly(A) sites] supported by cDNA/EST sequences. The polyadenylation pattern in the 3'- most exon defines the 3' UnTranslated Region (UTR), which contains various cis regulatory elements for mRNA metabolism, such as microRNA (miRNA) target sites and AU-rich elements (AUEs). In addition, a large fraction of human genes have polyadenylation events in introns, leading to mRNA variants with different protein coding sequence and indicating dynamic interplay between polyadenylation and splicing. Regulation of gene expression by polyadenylation has been characterized only for a handful of model genes, and its mechanism is poorly understood on the systems level. The long-term goal is to understand the mechanisms by which mRNA polyadenylation regulates gene expression in eukaryotic genomes. There are two specific aims in this project: 1) To accurately predict poly(A) sites across metazoan species using their corresponding cis elements; 2) To quantitatively model poly(A) site usage and selection across human and mouse tissues. We will combine computational and molecular biology techniques to address these issues. The results will improve gene annotation in metazoan species, uncover gene regulation events mediated by alternative polyadenylation, elucidate 3' UTR evolution, shed light on the mechanisms of polyadenylation, and provide valuable tools to examine human mutations and polymorphisms that affect poly(A) sites. NARRATIVE mRNA polyadenylation is an essential step for the maturation of almost all eukaryotic mRNAs. Altered polyadenylation activity caused by genetic mutation has been implicated in a growing number of human diseases. Over half of the human genes contain multiple polyadenylation sites [poly(A) sites] supported by cDNA/EST sequences. The polyadenylation pattern in the 3'- most exon defines the 3' UnTranslated Region (UTR), which contains various cis regulatory elements for mRNA metabolism, such as microRNA (miRNA) target sites and AU-rich elements (AUEs). In addition, a large fraction of human genes have polyadenylation events in introns, leading to mRNA variants with different protein coding sequence and indicating dynamic interplay between polyadenylation and splicing. Regulation of gene expression by polyadenylation has been characterized only for a handful of model genes, and its mechanism is poorly understood on the systems level. The long term goal is to understand the mechanisms by which mRNA polyadenylation regulates gene expression in eukaryotic genomes. There are two specific aims in this project: 1) To accurately predict poly(A) sites across metazoan species using their corresponding cis elements; 2) To quantitatively model poly(A) site usage and selection across human and mouse tissues. We will combine computational and molecular biology techniques to address these issues. The results will improve gene annotation in metazoan species, uncover gene regulation events mediated by alternative polyadenylation, elucidate 3' UTR evolution, shed light on the mechanisms of polyadenylation, and provide valuable tools to examine human mutations and polymorphisms that affect poly(A) sites.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
6R01GM084089-07
Application #
8720197
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
2013-07-01
Budget End
2014-04-30
Support Year
Fiscal Year
2013
Total Cost
$286,896
Indirect Cost
$106,458
Name
Rutgers University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
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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