Abstract

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.

Public Health Relevance

miRNAs and endogenous siRNAs are key biological regulators like transcription factors. As more and more miRNAs are discovered to be involved in diseases as diverse as heart disease and cancer, the mechanism by which they regulate target genes will become central to more fields. 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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM044619-26
Application #
9405879
Study Section
Molecular Genetics B Study Section (MGB)
Program Officer
Bender, Michael T
Project Start
1991-05-01
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
26
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code

  Publications

Newman, Martin A; Ji, Fei; Fischer, Sylvia E J et al. (2018) The surveillance of pre-mRNA splicing is an early step in C. elegans RNAi of endogenous genes. Genes Dev 32:670-681
Ambros, Victor; Ruvkun, Gary (2018) Recent Molecular Genetic Explorations of Caenorhabditis elegans MicroRNAs. Genetics 209:651-673
Dowen, Robert H; Breen, Peter C; Tullius, Thomas et al. (2016) A microRNA program in the C. elegans hypodermis couples to intestinal mTORC2/PQM-1 signaling to modulate fat transport. Genes Dev 30:1515-28
Phillips, Carolyn M; Brown, Kristen C; Montgomery, Brooke E et al. (2015) piRNAs and piRNA-Dependent siRNAs Protect Conserved and Essential C. elegans Genes from Misrouting into the RNAi Pathway. Dev Cell 34:457-65
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
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
Tabach, Yuval; Golan, Tamar; Hernández-Hernández, Abrahan et al. (2013) Human disease locus discovery and mapping to molecular pathways through phylogenetic profiling. Mol Syst Biol 9:692
Fischer, Sylvia E J; Pan, Qi; Breen, Peter C et al. (2013) Multiple small RNA pathways regulate the silencing of repeated and foreign genes in C. elegans. Genes Dev 27:2678-95
Shi, Zhen; Hayes, Gabriel; Ruvkun, Gary (2013) Dual regulation of the lin-14 target mRNA by the lin-4 miRNA. PLoS One 8:e75475
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

Showing the most recent 10 out of 33 publications