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  Dissecting dual roles of MyoD during lineage conversion to mature myocytes and myogenic stem cells

Yagi, M., Ji, F., Charlton, J., Cristea, S., Messemer, K., Horwitz, N., et al. (2021). Dissecting dual roles of MyoD during lineage conversion to mature myocytes and myogenic stem cells. Genes and Development, 35(17-18), 1209-1228. doi:10.1101/gad.348678.121.

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 Creators:
Yagi , Masaki , Author
Ji, Fei, Author
Charlton, Jocelyn1, Author              
Cristea, Simona , Author
Messemer, Kathleen , Author
Horwitz, Naftali , Author
Di Stefano, Bruno, Author
Tsopoulidis, Nikolaos , Author
Hoetker, Michael S. , Author
Huebner, Aaron J. , Author
Bar-Nur, Ori, Author
Almada, Albert E., Author
Yamamoto, Masakazu, Author
Patelunas, Anthony , Author
Goldhamer, David J. , Author
Wagers, Amy J. , Author
Michor, Franziska , Author
Meissner, Alexander1, Author              
Sadreyev, Ruslan I., Author
Hochedlinger, Konrad , Author
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              

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Free keywords: DNA methylation; MyoD; dedifferentiation; epigenetic reprogramming; induced myogenic progenitor cells (iMPCs); satellite cells; transdifferentiation
 Abstract: 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.

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Language(s): eng - English
 Dates: 2021-08-022021-08-192021-09-01
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1101/gad.348678.121
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Title: Genes and Development
Source Genre: Journal
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Publ. Info: Cold Spring Harbor Laboratory Press
Pages: - Volume / Issue: 35 (17-18) Sequence Number: - Start / End Page: 1209 - 1228 Identifier: ISSN: 0890-9369
CoNE: https://pure.mpg.de/cone/journals/resource/954925557453