Transcription Factors And Skeletal Muscle : New insights on the TEAD4 transcription factor

The TEAD family of transcription factors is composed of 4 paralogous genes (TEAD1-4) that regulate developmental processes, including myogenesis, and oncogenesis. In this thesis, we show that shRNA-mediated TEAD4 silencing in C2C12 cells causes differentiation defects characterized by shortened myotubes. We performed chromatin immunoprecipitation (ChIP) experiments coupled with hybridization to DNA microarrays (ChIP-chip) to identify TEAD4 target genes as well as RNA-seq to identify TEAD4 transcriptional regulatory network. TEAD4 occupies the promoters of 929 genes, including those of MyoD1 and Myogenin, and myogenic microRNAs. We show that TEAD4 directly induces expression of Myogenin, CDKN1A and Caveolin 3 to promote C2C12 cells differentiation. RNA-seq identifies a set of genes whose expression is strongly reduced upon TEAD4 knockdown amongst which are muscle structural and regulatory proteins and those required for the unfolded protein response (UPR). Preliminary analysis of TEAD4 expression in mouse skeletal muscle during regeneration corroborated these findings. Our study furthers the understanding of the TEAD4 function in the physiopathology of skeletal muscle.