Dissecting dual roles of MyoD during lineage conversion to mature myocytes and myogenic stem cells
| Autor: | Simona Cristea, Fei Ji, Michael S. Hoetker, Bruno Di Stefano, Ruslan I. Sadreyev, Masakazu Yamamoto, Kathleen A. Messemer, Alexander Meissner, Aaron J. Huebner, Franziska Michor, Masaki Yagi, Naftali Horwitz, Anthony Patelunas, David J. Goldhamer, A. Almada, Nikolaos Tsopoulidis, Konrad Hochedlinger, Jocelyn Charlton, Ori Bar-Nur, Amy J. Wagers |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
induced myogenic progenitor cells (iMPCs)
transdifferentiation Muscle Fibers Skeletal epigenetic reprogramming Biology MyoD Muscle Development dedifferentiation satellite cells DNA methylation Myoblasts Mice Genetics Animals Epigenetics Progenitor cell Muscle Skeletal MyoD Protein Myogenesis Stem Cells Transdifferentiation Cell Differentiation Cell biology Stem cell Reprogramming Developmental Biology Research Paper |
| Zdroj: | Genes Dev Genes and Development Genes & Development, 35 (17-18) |
| ISSN: | 0890-9369 1549-5477 |
| DOI: | 10.3929/ethz-b-000505029 |
| Popis: | The generation of myotubes from fibroblasts upon forced MyoD expression is a classic example of transcription factor-induced reprogramming. We recently discovered that additional modulation of signaling pathways with small molecules facilitates reprogramming to more primitive induced myogenic progenitor cells (iMPCs). Here, we dissected the transcriptional and epigenetic dynamics of mouse fibroblasts undergoing reprogramming to either myotubes or iMPCs using a MyoD-inducible transgenic model. Induction of MyoD in fibroblasts combined with small molecules generated Pax7(+) iMPCs with high similarity to primary muscle stem cells. Analysis of intermediate stages of iMPC induction revealed that extinction of the fibroblast program preceded induction of the stem cell program. Moreover, key stem cell genes gained chromatin accessibility prior to their transcriptional activation, and these regions exhibited a marked loss of DNA methylation dependent on the Tet enzymes. In contrast, myotube generation was associated with few methylation changes, incomplete and unstable reprogramming, and an insensitivity to Tet depletion. Finally, we showed that MyoD's ability to bind to unique bHLH targets was crucial for generating iMPCs but dispensable for generating myotubes. Collectively, our analyses elucidate the role of MyoD in myogenic reprogramming and derive general principles by which transcription factors and signaling pathways cooperate to rewire cell identity. Genes & Development, 35 (17-18) ISSN:0890-9369 ISSN:1549-5477 |
| Databáze: | OpenAIRE |
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