Functional genomic analysis of the let-7 regulatory network in Caenorhabditis elegans

• Published in: PLoS genetics 2013-03, Vol.9 (3), p.e1003353
• Main Authors: Hunter, Shaun E, Finnegan, Emily F, Zisoulis, Dimitrios G, Lovci, Michael T, Melnik-Martinez, Katya V, Yeo, Gene W, Pasquinelli, Amy E
• Format: Article
• Language: English
• Subjects: Animal development; Animals; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Binding sites; Biology; Caenorhabditis elegans; Caenorhabditis elegans - genetics; Caenorhabditis elegans - growth & development; Caenorhabditis elegans Proteins - genetics; Caenorhabditis elegans Proteins - metabolism; Cell Differentiation; Cell division; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cellular control mechanisms; Gene expression; Gene Expression Regulation, Developmental; Gene Regulatory Networks; Genetic aspects; Genetics; Genome; Genomes; Humans; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Mutation; Phenotype; Properties; Proteins; Regulation; RNA polymerase
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1003353

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.