The L27 domain of MPP7 enhances TAZ-YY1 cooperation to renew muscle stem cells

Stem cells regenerate differentiated cells to maintain and repair tissues and organs. They also replenish themselves, i.e. self-renew, to support a lifetime of regenerative capacity. Here we study the renewal of skeletal muscle stem cell (MuSC) during regeneration. The transcriptional co-factors TAZ/YAP (via the TEAD transcription factors) regulate cell cycle and growth while the transcription factor YY1 regulates metabolic programs for MuSC activation. We show that MPP7 and AMOT join TAZ and YY1 to regulate a selected number of common genes that harbor TEAD and YY1 binding sites. Among these common genes, Carm1 can direct MuSC renewal. We demonstrate that the L27 domain of MPP7 enhances the interaction as well as the transcriptional activity of TAZ and YY1, while AMOT acts as an intermediate to bridge them together. Furthermore, MPP7, TAZ and YY1 co-occupy the promoters of Carm1 and other common downstream genes. Our results define a renewal program comprised of two progenitor transcriptional programs, in which selected key genes are regulated by protein-protein interactions, dependent on promoter context. Synopsis Renewal divisions of muscle stem cells are regulated by the methyltransferase CARM1. This study shows that Carm1 is transcriptionally regulated by the coordinated action of MPP7, AMOT, YAP/TAZ, and YY1. Mpp7 cKO and Amot cKO mice display similar muscle stem cell renewal defects. Mpp7 cKO, Amot cKO, and Yap/Taz double cKO transcriptomes reveal a common set of down-regulated genes, including Carm1. MPP7, AMOT, YAP/TAZ, and YY1 form a protein complex to activate Carm1 transcription. The L27 domain of MPP7 facilitates complex formation and contributes to the enhanced transcriptional activity. Renewal divisions of muscle stem cells are regulated by the methyltransferase CARM1. This study shows that Carm1 is transcriptionally regulated by the coordinated action of MPP7, AMOT, YAP/TAZ, and YY1.