The role that RNA molecules play during eukaryotic gene expression has moved to center stage. Land plants, mammals, and other bilateral animals each have from ~100 to >400 genes that produce ~22-nt noncoding RNAs, called microRNAs (miRNAs). MicroRNAs pair to the mRNAs of protein-coding genes to direct the posttranscriptional repression of these messages. Because a single mammalian miRNA can target hundreds of messages, miRNAs have a widespread impact on mRNA repression and evolution. This proposal focuses on the genomics and functional genomics of this newly identified class of genes, with the broad, long-term objective of understanding the roles of RNA in regulating gene expression.
The specific aims are: 1) to identify additional miRNA genes, 2) to improve and expand miRNA target identification, and 3) to determine the molecular consequences of miRNA-mediated repression. Experiments of Aim #1 will use high-throughput sequencing to identify many miRNA genes, including previously unrecognized human genes, substantially increasing (and correcting) annotations of this gene class. Gene discovery will also be extended to basal animals, including sponge and cnideria, to shed light on the evolutionary origins of this mode of gene regulation. Experiments of Aim #2 will use molecular and comparative genomic approaches to provide a more precise and comprehensive list of predicted targets a resource for all biologists, and of particular value for those concerned with eukaryotic gene regulation, development, and disease. Experiments of Aim #3 will determine the extent to which miRNA-mediated repression can be discerned from reduced transcript accumulation. They also will likely identify many new targets beyond those currently detected on mRNA expression arrays and thereby provide large, quantitative datasets needed for improving and expanding target predictions. Because more than a third of the human genes have been under selective pressure to maintain their pairing to a set of broadly conserved miRNAs, it is no surprise that miRNAs have already been shown to play important roles in mammalian development, viral infection, and cancer. Knowing the miRNA genes, their likely targets, and the molecular consequences of their action will be useful for determining additional functions of miRNAs and learning how their dysfunction can contribute to human disease. Public Health Relevance: The experiments of this proposal focus on short snippets of RNA called microRNAs, which can collaborate with the proteins of the cell to determine how much protein is produced from individual genes, including many genes implicated in cancer and other diseases. The goals are to find microRNAs that had gone unrecognized, to learn how best to predict which genes the microRNAs regulate, and to determine the magnitude of their effects on protein output. Achieving these goals will shed light on why microRNAs are needed for normal growth and development, and how their dysfunction can contribute to human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM067031-07
Application #
7793483
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Bender, Michael T
Project Start
2002-09-03
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
7
Fiscal Year
2010
Total Cost
$706,898
Indirect Cost
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
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Eichhorn, Stephen W; Subtelny, Alexander O; Kronja, Iva et al. (2016) mRNA poly(A)-tail changes specified by deadenylation broadly reshape translation in Drosophila oocytes and early embryos. Elife 5:
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Agarwal, Vikram; Bell, George W; Nam, Jin-Wu et al. (2015) Predicting effective microRNA target sites in mammalian mRNAs. Elife 4:
Hezroni, Hadas; Koppstein, David; Schwartz, Matthew G et al. (2015) Principles of long noncoding RNA evolution derived from direct comparison of transcriptomes in 17 species. Cell Rep 11:1110-22
Nam, Jin-Wu; Rissland, Olivia S; Koppstein, David et al. (2014) Global analyses of the effect of different cellular contexts on microRNA targeting. Mol Cell 53:1031-1043
Denzler, Rémy; Agarwal, Vikram; Stefano, Joanna et al. (2014) Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. Mol Cell 54:766-76
Kronja, Iva; Yuan, Bingbing; Eichhorn, Stephen W et al. (2014) Widespread changes in the posttranscriptional landscape at the Drosophila oocyte-to-embryo transition. Cell Rep 7:1495-1508

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