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 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.
Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
Steven G
SG
Kuntz
Brian A
BA
Williams
Paul W
PW
Sternberg
Barbara J
BJ
Wold
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D026161:MADS Domain Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins; D009132:Muscles / Q000378:metabolism; D009154:Mutation; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins; D059372:Nucleotide Motifs; D009928:Organ Specificity / Q000235:genetics*; D011485:Protein Binding; D034622:RNA Interference; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
D029742:Caenorhabditis elegans Proteins; D026161:MADS Domain Proteins; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; C516540:UNC-120 protein, C elegans; C066645:HLH-1 protein, C elegans