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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. (2020). Permissive epigenomes endow reprogramming competence to transcriptional regulators. Nature Chemical Biology, In Press. doi:10.1038/s41589-020-0618-6.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0006-E53C-5 Version Permalink: http://hdl.handle.net/21.11116/0000-0006-E704-1
Genre: Journal Article

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 Creators:
Kim, K.-P., Author
Choi, J.1, Author              
Yoon, J., Author
Bruder, J. M., Author
Shin, B., Author
Kim, J., Author
Arauzo-Bravo, M. J., Author
Han, D., Author
Wu, G., Author
Han, D. W., Author
Kim, J., Author
Cramer, P.1, Author              
Schöler, H. R., Author
Affiliations:
1Department of Molecular Biology, MPI for Biophysical Chemistry, Max Planck Society, ou_1863498              

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Free keywords: Chromatin remodelling, Screening, Small molecules, Stem cells, Transcription
 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.

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Language(s): eng - English
 Dates: 2020-08-17
 Publication Status: Published online
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 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41589-020-0618-6
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Title: Nature Chemical Biology
Source Genre: Journal
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