The homeobox gene Mohawk represses transcription by recruiting the Sin3A/HDAC co-repressor complex

Mohawk is an atypical homeobox gene expressed in embryonic progenitor cells of skeletal muscle, tendon, and cartilage. We demonstrate that Mohawk functions as a transcriptional repressor capable of blocking the myogenic conversion of 10T1/2 fibroblasts. The repressor activity is located in three small, evolutionarily conserved domains (MRD1-3) in the carboxy-terminal half of the protein. Point mutation analysis revealed six residues in MRD1 are sufficient for repressor function. The carboxy-terminal half of Mohawk is able to recruit components of the Sin3A/HDAC co-repressor complex (Sin3A, Hdac1, and Sap18) and a subset of Polymerase II general transcription factors (Tbp, TFIIA1 and TFIIB). Furthermore, Sap18, a protein that bridges the Sin3A/HDAC complex to DNA-bound transcription factors, is coimmunoprecipitated by MRD1. These data predict that Mohawk can repress transcription through recruitment of the Sin3A/HDAC co-repressor complex, and as a result, repress target genes required for the differentiation of cells to the myogenic lineage.