title: Transcription factor TEAD4 regulates expression of myogenin and the unfolded protein response genes during C2C12 cell differentiation.
abstract: The TEAD (1-4) transcription factors comprise the conserved TEA/ATTS DNA-binding domain recognising the MCAT element in the promoters of muscle-specific genes. Despite extensive genetic analysis, the function of TEAD factors in muscle differentiation has proved elusive due to redundancy among the family members. Expression of the TEA/ATTS DNA-binding domain that acts as a dominant negative repressor of TEAD factors in C2C12 myoblasts inhibits their differentiation, whereas selective shRNA knockdown of TEAD4 results in abnormal differentiation characterised by the formation of shortened myotubes. Chromatin immunoprecipitation coupled to array hybridisation shows that TEAD4 occupies 867 promoters including those of myogenic miRNAs. We show that TEAD factors directly induce Myogenin, CDKN1A and Caveolin 3 expression to promote myoblast differentiation. RNA-seq identifies a set of genes whose expression is strongly reduced upon TEAD4 knockdown among which are structural and regulatory proteins and those required for the unfolded protein response. In contrast, TEAD4 represses expression of the growth factor CTGF (connective tissue growth factor) to promote differentiation. Together these results show that TEAD factor activity is essential for normal C2C12 cell differentiation and suggest a role for TEAD4 in regulating expression of the unfolded protein response genes.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UDS, 1 Rue Laurent Fries, 67404 Illkirch Cédex, France.
authors.forename: A
authors.initials: A
authors.lastname: Benhaddou
authors.forename: C
authors.initials: C
authors.lastname: Keime
authors.forename: T
authors.initials: T
authors.lastname: Ye
authors.forename: A
authors.initials: A
authors.lastname: Morlon
authors.forename: I
authors.initials: I
authors.lastname: Michel
authors.forename: B
authors.initials: B
authors.lastname: Jost
authors.forename: G
authors.initials: G
authors.lastname: Mengus
authors.forename: I
authors.initials: I
authors.lastname: Davidson
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D002459:Cell Fusion; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D051379:Mice; D008969:Molecular Sequence Data; D024510:Muscle Development / Q000235:genetics; D009124:Muscle Proteins / Q000378:metabolism*; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D018008:Myogenin / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000235:genetics*
chemical_list: C526318:CCN2 protein, mouse; C530105:Ccnd1 protein, mouse; D004268:DNA-Binding Proteins; D009124:Muscle Proteins; D018008:Myogenin; D012097:Repressor Proteins; D000091262:TEA Domain Transcription Factors; C101204:Tead4 protein, mouse; D014157:Transcription Factors; D019938:Cyclin D1; D055513:Connective Tissue Growth Factor