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
7
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
Elbarbary, Reyad A; Miyoshi, Keita; Myers, Jason R et al. (2017) Tudor-SN-mediated endonucleolytic decay of human cell microRNAs promotes G1/S phase transition. Science 356:859-862
Ogami, Koichi; Richard, Patricia; Chen, Yaqiong et al. (2017) An Mtr4/ZFC3H1 complex facilitates turnover of unstable nuclear RNAs to prevent their cytoplasmic transport and global translational repression. Genes Dev :
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
Liu, Xiaochuan; Hoque, Mainul; Larochelle, Marc et al. (2017) Comparative analysis of alternative polyadenylation in S. cerevisiae and S. pombe. Genome Res 27:1685-1695
Tian, Bin; Manley, James L (2017) Alternative polyadenylation of mRNA precursors. Nat Rev Mol Cell Biol 18:18-30
Fontes, Mariana M; Guvenek, Aysegul; Kawaguchi, Riki et al. (2017) Activity-Dependent Regulation of Alternative Cleavage and Polyadenylation During Hippocampal Long-Term Potentiation. Sci Rep 7:17377
Li, Weimin; Li, Wencheng; Laishram, Rakesh S et al. (2017) Distinct regulation of alternative polyadenylation and gene expression by nuclear poly(A) polymerases. Nucleic Acids Res 45:8930-8942
Shi, Min; Zhang, Heng; Wu, Xudong et al. (2017) ALYREF mainly binds to the 5' and the 3' regions of the mRNA in vivo. Nucleic Acids Res 45:9640-9653

Showing the most recent 10 out of 56 publications