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  Permissive epigenomes endow reprogramming competence to transcriptional regulators

Kim, K.-P., Choi, J., Yoon, J., Bruder, J. M., Shin, B., Kim, J., et al. (2021). Permissive epigenomes endow reprogramming competence to transcriptional regulators. NATURE CHEMICAL BIOLOGY, 17(1), 47-56. doi:10.1038/s41589-020-0618-6.

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 Creators:
Kim, Kee-Pyo, Author
Choi, Jinmi, Author
Yoon, Juyong, Author
Bruder, Jan M., Author
Shin, Borami, Author
Kim, Jonghun, Author
Arauzo-Bravo, Marcos J., Author
Han, Dong, Author
Wu, Guangming, Author
Han, Dong Wook, Author
Kim, Johnny1, Author              
Cramer, Patrick, Author
Schoeler, Hans R., Author
Affiliations:
1Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Max Planck Society, ou_2591695              

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 Abstract: Identifying molecular and cellular processes that regulate reprogramming competence of transcription factors broadens our understanding of reprogramming mechanisms. In the present study, by a chemical screen targeting major epigenetic pathways in human reprogramming, we discovered that inhibiting specific epigenetic roadblocks including disruptor of telomeric silencing 1-like (DOT1L)-mediated H3K79/K27 methylation, but also other epigenetic pathways, catalyzed by lysine-specific histone demethylase 1A, DNA methyltransferases and histone deacetylases, allows induced pluripotent stem cell generation with almost all OCT factors. We found that simultaneous inhibition of these pathways not only dramatically enhances reprogramming competence of most OCT factors, but in fact enables dismantling of species-dependent reprogramming competence of OCT6, NR5A1, NR5A2, TET1 and GATA3. Harnessing these induced permissive epigenetic states, we performed an additional screen with 98 candidate genes. Thereby, we identified 25 transcriptional regulators (OTX2, SIX3, and so on) that can functionally replace OCT4 in inducing pluripotency. Our findings provide a conceptual framework for understanding how transcription factors elicit reprogramming in dependency of the donor cell epigenome that differs across species. A chemical screen targeting major epigenetic pathways identifies permissive epigenetic states that enable reprogramming with a broad range of transcriptional regulators and almost all octamer-binding (OCT) family members.

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 Dates: 2020-08-172021-01
 Publication Status: Published in print
 Pages: -
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 Rev. Type: -
 Identifiers: ISI: 000724126200002
DOI: 10.1038/s41589-020-0618-6
PMID: 32807969
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Title: NATURE CHEMICAL BIOLOGY
Source Genre: Journal
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Pages: - Volume / Issue: 17 (1) Sequence Number: - Start / End Page: 47 - 56 Identifier: ISSN: 1552-4450