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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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:	Online
Language:	English
Published:	Genetics Society of America 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025478/

id	pubmed-4025478
recordtype	oai_dc
spelling	pubmed-40254782014-05-30 A Complex Regulatory Network Coordinating Cell Cycles During C. elegans Development Is Revealed by a Genome-Wide RNAi Screen 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 Investigations 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. Genetics Society of America 2014-02-28 /pmc/articles/PMC4025478/ /pubmed/24584095 http://dx.doi.org/10.1534/g3.114.010546 Text en Copyright © 2014 Roy et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Unported License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	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
spellingShingle	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 A Complex Regulatory Network Coordinating Cell Cycles During C. elegans Development Is Revealed by a Genome-Wide RNAi Screen
author_facet	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
author_sort	Roy, Sarah H.
title	A Complex Regulatory Network Coordinating Cell Cycles During C. elegans Development Is Revealed by a Genome-Wide RNAi Screen
title_short	A Complex Regulatory Network Coordinating Cell Cycles During C. elegans Development Is Revealed by a Genome-Wide RNAi Screen
title_full	A Complex Regulatory Network Coordinating Cell Cycles During C. elegans Development Is Revealed by a Genome-Wide RNAi Screen
title_fullStr	A Complex Regulatory Network Coordinating Cell Cycles During C. elegans Development Is Revealed by a Genome-Wide RNAi Screen
title_full_unstemmed	A Complex Regulatory Network Coordinating Cell Cycles During C. elegans Development Is Revealed by a Genome-Wide RNAi Screen
title_sort	complex regulatory network coordinating cell cycles during c. elegans development is revealed by a genome-wide rnai screen
description	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.
publisher	Genetics Society of America
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4025478/
_version_	1612090539789778944

A Complex Regulatory Network Coordinating Cell Cycles During C. elegans Development Is Revealed by a Genome-Wide RNAi Screen

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