Shao Anwen, Kissil Joseph L, Fan Chen-Ming
Department of Embryology, Carnegie Institution for Science, 3520 San Martin Drive, Baltimore, MD, 21218, USA.
Department of Molecular Oncology, The H. Lee Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL, 33612, USA.
EMBO Rep. 2024 Dec;25(12):5667-5686. doi: 10.1038/s44319-024-00305-4. Epub 2024 Nov 4.
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.
干细胞再生分化细胞以维持和修复组织与器官。它们还能自我补充，即自我更新，以支持终身的再生能力。在此，我们研究骨骼肌干细胞（MuSC）在再生过程中的更新。转录共因子TAZ/YAP（通过TEAD转录因子）调节细胞周期和生长，而转录因子YY1调节MuSC激活的代谢程序。我们发现MPP7和AMOT与TAZ和YY1共同调节一定数量带有TEAD和YY1结合位点的共同基因。在这些共同基因中，Carm1可指导MuSC更新。我们证明MPP7的L27结构域增强了TAZ和YY1的相互作用以及转录活性，而AMOT作为中间体将它们连接在一起。此外，MPP7、TAZ和YY1共同占据Carm1和其他共同下游基因的启动子。我们的结果定义了一个由两个祖细胞转录程序组成的更新程序，其中选定的关键基因通过蛋白质-蛋白质相互作用进行调节，这取决于启动子背景。
