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

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...

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Autores principales: Kuntz, Steven G., Williams, Brian A., Sternberg, Paul W., Wold, Barbara J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460186/
https://www.ncbi.nlm.nih.gov/pubmed/22730465
http://dx.doi.org/10.1101/gr.133306.111
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author Kuntz, Steven G.
Williams, Brian A.
Sternberg, Paul W.
Wold, Barbara J.
author_facet Kuntz, Steven G.
Williams, Brian A.
Sternberg, Paul W.
Wold, Barbara J.
author_sort Kuntz, Steven G.
collection PubMed
description 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.
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spelling pubmed-34601862013-04-01 Transcription factor redundancy and tissue-specific regulation: Evidence from functional and physical network connectivity Kuntz, Steven G. Williams, Brian A. Sternberg, Paul W. Wold, Barbara J. Genome Res Research 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. Cold Spring Harbor Laboratory Press 2012-10 /pmc/articles/PMC3460186/ /pubmed/22730465 http://dx.doi.org/10.1101/gr.133306.111 Text en © 2012, Published by Cold Spring Harbor Laboratory Press This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.
spellingShingle Research
Kuntz, Steven G.
Williams, Brian A.
Sternberg, Paul W.
Wold, Barbara J.
Transcription factor redundancy and tissue-specific regulation: Evidence from functional and physical network connectivity
title Transcription factor redundancy and tissue-specific regulation: Evidence from functional and physical network connectivity
title_full Transcription factor redundancy and tissue-specific regulation: Evidence from functional and physical network connectivity
title_fullStr Transcription factor redundancy and tissue-specific regulation: Evidence from functional and physical network connectivity
title_full_unstemmed Transcription factor redundancy and tissue-specific regulation: Evidence from functional and physical network connectivity
title_short Transcription factor redundancy and tissue-specific regulation: Evidence from functional and physical network connectivity
title_sort transcription factor redundancy and tissue-specific regulation: evidence from functional and physical network connectivity
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460186/
https://www.ncbi.nlm.nih.gov/pubmed/22730465
http://dx.doi.org/10.1101/gr.133306.111
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