We have identified a number of genes via genetic analysis and RNA interference gene inactivations that act as protein coding cofactors for the function of miRNAs and siRNAs in C. elegans. Some of these proteins were identified in genetic screens for decrease in miRNA function, some in genetic screens for decrease in siRNA function, and some in genetic screens for increase in siRNA function. We have also identified the target small RNAs that mediate these functions by deep RNA sequencing of selected mutant strains. We propose to dissect in detail how these proteins orchestrate the production, trafficking, and function of small RNAs in both mRNA degradation, mRNA translational control, and control of gene expression. We also propose to discern how the miRNA and siRNA and other small RNA pathways may compete with each other for common cofactors, thus leading to an increase in function in one pathway, when the other pathway is debilitated. The genes identified in this study are likely to be key factors in the function of small RNAs in biology and thus their identification may enable more potent RNAi based drug development.

Public Health Relevance

The Ruvkun lab has identified a large collection of genes that act as cofactors for the function of small RNA genes in C. elegans. We propose to dissect in detail how these proteins orchestrate the production, trafficking, and function of small RNAs in control of gene expression. The genes identified in this study are likely to be key factors in the function of small RNAs in biology and thus their identification may enable more potent RNA interference-based drug development.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM044619-22
Application #
8502670
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Bender, Michael T
Project Start
1991-05-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
22
Fiscal Year
2013
Total Cost
$636,391
Indirect Cost
$270,649
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Phillips, Carolyn M; Montgomery, Brooke E; Breen, Peter C et al. (2014) MUT-14 and SMUT-1 DEAD box RNA helicases have overlapping roles in germline RNAi and endogenous siRNA formation. Curr Biol 24:839-44
Tabach, Yuval; Golan, Tamar; Hernandez-Hernandez, Abrahan et al. (2013) Human disease locus discovery and mapping to molecular pathways through phylogenetic profiling. Mol Syst Biol 9:692
Tabach, Yuval; Billi, Allison C; Hayes, Gabriel D et al. (2013) Identification of small RNA pathway genes using patterns of phylogenetic conservation and divergence. Nature 493:694-8
Shi, Zhen; Hayes, Gabriel; Ruvkun, Gary (2013) Dual regulation of the lin-14 target mRNA by the lin-4 miRNA. PLoS One 8:e75475
Shi, Zhen; Montgomery, Taiowa A; Qi, Yan et al. (2013) High-throughput sequencing reveals extraordinary fluidity of miRNA, piRNA, and siRNA pathways in nematodes. Genome Res 23:497-508
Zhang, Chi; Montgomery, Taiowa A; Fischer, Sylvia E J et al. (2012) The Caenorhabditis elegans RDE-10/RDE-11 complex regulates RNAi by promoting secondary siRNA amplification. Curr Biol 22:881-90
Shi, Zhen; Ruvkun, Gary (2012) The mevalonate pathway regulates microRNA activity in Caenorhabditis elegans. Proc Natl Acad Sci U S A 109:4568-73
Montgomery, Taiowa A; Rim, Young-Soo; Zhang, Chi et al. (2012) PIWI associated siRNAs and piRNAs specifically require the Caenorhabditis elegans HEN1 ortholog henn-1. PLoS Genet 8:e1002616
Fischer, Sylvia E J; Montgomery, Taiowa A; Zhang, Chi et al. (2011) The ERI-6/7 helicase acts at the first stage of an siRNA amplification pathway that targets recent gene duplications. PLoS Genet 7:e1002369
Hayes, Gabriel D; Riedel, Christian G; Ruvkun, Gary (2011) The Caenorhabditis elegans SOMI-1 zinc finger protein and SWI/SNF promote regulation of development by the mir-84 microRNA. Genes Dev 25:2079-92

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