A complex regulatory network coordinating cell cycles during C. elegans development is revealed by a genome-wide RNAi screen

The development and homeostasis of multicellular animals requires precise coordination of cell division and differentiation. We performed a genome-wide RNA interference screen in Caenorhabditis elegans to reveal the components of a regulatory network that promotes developmentally programmed cell-cyc...

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Published in:	G3 : genes - genomes - genetics Vol. 4; no. 5; pp. 795 - 804
Main Authors:	Roy, Sarah H, Tobin, David V, Memar, Nadin, Beltz, Eleanor, Holmen, Jenna, Clayton, Joseph E, Chiu, Daniel J, Young, Laura D, Green, Travis H, Lubin, Isabella, Liu, Yuying, Conradt, Barbara, Saito, R Mako
Format:	Journal Article
Language:	English
Published:	England Genetics Society of America 01-05-2014
Subjects:	Animals Caenorhabditis elegans - genetics Caenorhabditis elegans - metabolism Caenorhabditis elegans Proteins - genetics Caenorhabditis elegans Proteins - metabolism Cell Cycle - genetics Cell Cycle Proteins - genetics Cell Cycle Proteins - metabolism Gene Expression Regulation, Developmental Gene Regulatory Networks Genome-Wide Association Study Investigations RNA Interference Ubiquitins - genetics Ubiquitins - metabolism C. elegans development intestine regulatory network cell cycle ubiquitin-conjugating enzyme
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Summary:	The development and homeostasis of multicellular animals requires precise coordination of cell division and differentiation. We performed a genome-wide RNA interference screen in Caenorhabditis elegans to reveal the components of a regulatory network that promotes developmentally programmed cell-cycle quiescence. The 107 identified genes are predicted to constitute regulatory networks that are conserved among higher animals because almost half of the genes are represented by clear human orthologs. Using a series of mutant backgrounds to assess their genetic activities, the RNA interference clones displaying similar properties were clustered to establish potential regulatory relationships within the network. This approach uncovered four distinct genetic pathways controlling cell-cycle entry during intestinal organogenesis. The enhanced phenotypes observed for animals carrying compound mutations attest to the collaboration between distinct mechanisms to ensure strict developmental regulation of cell cycles. Moreover, we characterized ubc-25, a gene encoding an E2 ubiquitin-conjugating enzyme whose human ortholog, UBE2Q2, is deregulated in several cancers. Our genetic analyses suggested that ubc-25 acts in a linear pathway with cul-1/Cul1, in parallel to pathways employing cki-1/p27 and lin-35/pRb to promote cell-cycle quiescence. Further investigation of the potential regulatory mechanism demonstrated that ubc-25 activity negatively regulates CYE-1/cyclin E protein abundance in vivo. Together, our results show that the ubc-25-mediated pathway acts within a complex network that integrates the actions of multiple molecular mechanisms to control cell cycles during development.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. Supporting information is available online at http://www.g3journal.org/lookup/suppl/doi:10.1534/g3.114.010546/-/DC1
ISSN:	2160-1836 2160-1836
DOI:	10.1534/g3.114.010546