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Transcription factor redundancy and tissue-specific regulation: Evidence from functional and physical network connectivity

Kuntz, Steven G. and Williams, Brian A. and Sternberg, Paul W. and Wold, Barbara J. (2012) Transcription factor redundancy and tissue-specific regulation: Evidence from functional and physical network connectivity. Genome Research, 22 (10). pp. 1907-1919. ISSN 1088-9051. PMCID PMC3460186.

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Two major transcriptional regulators of Caenorhabditis elegans bodywall muscle (BWM) differentiation, hlh-1 and unc-120, are expressed in muscle where they are known to bind and regulate several well-studied muscle-specific genes. Simultaneously mutating both factors profoundly inhibits formation of contractile BWM. These observations were consistent with a simple network model in which the muscle regulatory factors drive tissue-specific transcription by binding selectively near muscle-specific targets to activate them. We tested this model by measuring the number, identity, and tissue-specificity of functional regulatory targets for each factor. Some joint regulatory targets (218) are BWM-specific and enriched for nearby HLH-1 binding. However, contrary to the simple model, the majority of genes regulated by one or both muscle factors are also expressed significantly in non-BWM tissues. We also mapped global factor occupancy by HLH-1, and created a genetic interaction map that identifies hlh-1 collaborating transcription factors. HLH-1 binding did not predict proximate regulatory action overall, despite enrichment for binding among BWM-specific positive regulatory targets of hlh-1. We conclude that these tissue-specific factors contribute much more broadly to the transcriptional output of muscle tissue than previously thought, offering a partial explanation for widespread HLH-1 occupancy. We also identify a novel regulatory connection between the BWM-specific hlh-1 network and the hlh-8/twist nonstriated muscle network. Finally, our results suggest a molecular basis for synthetic lethality in which hlh-1 and unc-120 mutant phenotypes are mutually buffered by joint additive regulation of essential target genes, with additional buffering suggested via newly identified hlh-1 interacting factors.

Item Type:Article
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URLURL TypeDescription CentralArticle
Sternberg, Paul W.0000-0002-7699-0173
Wold, Barbara J.0000-0003-3235-8130
Additional Information:© 2012 Published by Cold Spring Harbor Laboratory Press. Received November 11, 2011; accepted in revised form May 24, 2012. Published in Advance June 22, 2012. Some nematode strains used in this work were provided by the the Caenorhabditis Genetics Center, funded by the NIH National Center for Research Resources (NCRR).We thank M. Krause for the anti-HLH-1 antibody, K. Fisher for her assistance in generating density graphs, S. Pepke for her assistance in generating conservation graphs, A. Kirilusha for his motif counter, H. Amrhein for assistance in managing genomic databases, M. Anaya and J. Vielmetter for purification of the antibody, I. Antoshechkin and L. Schaeffer for library making and sequencing, J. DeModena for assistance in obtaining reagents and helping grow worms, and Wormbase. This work was supported by NIGMS (GM084389 to P.W.S. and B.J.W.), the HHMI, with which P.W.S. is an investigator, the National Human Genome Research Institute (NHGRI), the Beckman Institute at Caltech, and the NCRR.
Funding AgencyGrant Number
National Institute of General Medical Sciences (NIGMS)GM084389
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
National Human Genome Research Institute (NHGRI)UNSPECIFIED
Caltech Beckman InstituteUNSPECIFIED
National Center for Research Resources (NCRR)UNSPECIFIED
Issue or Number:10
PubMed Central ID:PMC3460186
Record Number:CaltechAUTHORS:20121102-133341484
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Official Citation:Transcription factor redundancy and tissue-specific regulation: Evidence from functional and physical network connectivity Steven G. Kuntz, Brian A. Williams, Paul W. Sternberg, and Barbara J. Wold Genome Res. October 2012 22: 1907-1919; Published in Advance June 22, 2012, doi:10.1101/gr.133306.111
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:35269
Deposited By: Tony Diaz
Deposited On:07 Nov 2012 23:50
Last Modified:09 Mar 2020 13:19

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