title: ZEB1 imposes a temporary stage-dependent inhibition of muscle gene expression and differentiation via CtBP-mediated transcriptional repression.
abstract: Skeletal muscle development is orchestrated by the myogenic regulatory factor MyoD, whose activity is blocked in myoblasts by proteins preventing its nuclear translocation and/or binding to G/C-centered E-boxes in target genes. Recent evidence indicates that muscle gene expression is also regulated at the cis level by differential affinity for DNA between MyoD and other E-box binding proteins during myogenesis. MyoD binds to G/C-centered E-boxes, enriched in muscle differentiation genes, in myotubes but not in myoblasts. Here, we used cell-based and in vivo Drosophila, Xenopus laevis, and mouse models to show that ZEB1, a G/C-centered E-box binding transcriptional repressor, imposes a temporary stage-dependent inhibition of muscle gene expression and differentiation via CtBP-mediated transcriptional repression. We found that, contrary to MyoD, ZEB1 binds to G/C-centered E-boxes in muscle differentiation genes at the myoblast stage but not in myotubes. Its knockdown results in precocious expression of muscle differentiation genes and acceleration of myotube formation. Inhibition of muscle genes by ZEB1 occurs via transcriptional repression and involves recruitment of the CtBP corepressor. Lastly, we show that the pattern of gene expression associated with muscle differentiation is accelerated in ZEB1(-/-) mouse embryos. These results set ZEB1 as an important regulator of the temporal pattern of gene expression controlling muscle differentiation.
authors: Group of Transcriptional Regulation of Gene Expression, IDIBAPS, Barcelona, Spain.
authors: Laura
authors: L
authors: Siles
authors: Ester
authors: E
authors: Sánchez-Tilló
authors: Jong-Won
authors: JW
authors: Lim
authors: Douglas S
authors: DS
authors: Darling
authors: Kristen L
authors: KL
authors: Kroll
authors: Antonio
authors: A
authors: Postigo
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D024721:E-Box Elements; D015870:Gene Expression; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D024510:Muscle Development / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D017570:MyoD Protein / Q000235:genetics / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014982:Xenopus laevis; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D017570:MyoD Protein; D012097:Repressor Proteins; D014157:Transcription Factors; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein