title: Functional genomic analysis of the let-7 regulatory network in Caenorhabditis elegans.
abstract: The let-7 microRNA (miRNA) regulates cellular differentiation across many animal species. Loss of let-7 activity causes abnormal development in Caenorhabditis elegans and unchecked cellular proliferation in human cells, which contributes to tumorigenesis. These defects are due to improper expression of protein-coding genes normally under let-7 regulation. While some direct targets of let-7 have been identified, the genome-wide effect of let-7 insufficiency in a developing animal has not been fully investigated. Here we report the results of molecular and genetic assays aimed at determining the global network of genes regulated by let-7 in C. elegans. By screening for mis-regulated genes that also contribute to let-7 mutant phenotypes, we derived a list of physiologically relevant potential targets of let-7 regulation. Twenty new suppressors of the rupturing vulva or extra seam cell division phenotypes characteristic of let-7 mutants emerged. Three of these genes, opt-2, prmt-1, and T27D12.1, were found to associate with Argonaute in a let-7-dependent manner and are likely novel direct targets of this miRNA. Overall, a complex network of genes with various activities is subject to let-7 regulation to coordinate developmental timing across tissues during worm development.
authors.affiliation: Division of Biology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Shaun E
authors.initials: SE
authors.lastname: Hunter
authors.forename: Emily F
authors.initials: EF
authors.lastname: Finnegan
authors.forename: Dimitrios G
authors.initials: DG
authors.lastname: Zisoulis
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lovci
authors.forename: Katya V
authors.initials: KV
authors.lastname: Melnik-Martinez
authors.forename: Gene W
authors.initials: GW
authors.lastname: Yeo
authors.forename: Amy E
authors.initials: AE
authors.lastname: Pasquinelli
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D016678:Genome; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010641:Phenotype
chemical_list: D018528:ATP-Binding Cassette Transporters; D029742:Caenorhabditis elegans Proteins; D035683:MicroRNAs; C474488:let-7 microRNA, C elegans; C113070:pept-1 protein, C elegans