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
Miles, Wayne O; Lembo, Antonio; Volorio, Angela et al. (2016) Alternative Polyadenylation in Triple-Negative Breast Tumors Allows NRAS and c-JUN to Bypass PUMILIO Posttranscriptional Regulation. Cancer Res 76:7231-7241
Li, Wencheng; Park, Ji Yeon; Zheng, Dinghai et al. (2016) Alternative cleavage and polyadenylation in spermatogenesis connects chromatin regulation with post-transcriptional control. BMC Biol 14:6
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
Yang, Yan; Li, Wencheng; Hoque, Mainul et al. (2016) PAF Complex Plays Novel Subunit-Specific Roles in Alternative Cleavage and Polyadenylation. PLoS Genet 12:e1005794
Yang, Qiyuan; Lin, Jimin; Liu, Miao et al. (2016) Highly sensitive sequencing reveals dynamic modifications and activities of small RNAs in mouse oocytes and early embryos. Sci Adv 2:e1501482
Tahmasebi, Soroush; Jafarnejad, Seyed Mehdi; Tam, Ingrid S et al. (2016) Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2. Proc Natl Acad Sci U S A 113:12360-12367
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
Zheng, Dinghai; Liu, Xiaochuan; Tian, Bin (2016) 3'READS+, a sensitive and accurate method for 3' end sequencing of polyadenylated RNA. RNA 22:1631-9
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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