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DOT1L is a barrier to histone acetylation during reprogramming to pluripotency
Embryonic stem cells (ESCs) have transcriptionally permissive chromatin enriched for gene activation–associated histone modifications. A striking exception is DOT1L-mediated H3K79 dimethylation (H3K79me2) that is considered a positive regulator of transcription. We find that ESCs are depleted for H3...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10656071/ https://www.ncbi.nlm.nih.gov/pubmed/37976354 http://dx.doi.org/10.1126/sciadv.adf3980 |
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author | Wille, Coral K. Zhang, Xiaoya Haws, Spencer A. Denu, John M. Sridharan, Rupa |
author_facet | Wille, Coral K. Zhang, Xiaoya Haws, Spencer A. Denu, John M. Sridharan, Rupa |
author_sort | Wille, Coral K. |
collection | PubMed |
description | Embryonic stem cells (ESCs) have transcriptionally permissive chromatin enriched for gene activation–associated histone modifications. A striking exception is DOT1L-mediated H3K79 dimethylation (H3K79me2) that is considered a positive regulator of transcription. We find that ESCs are depleted for H3K79me2 at shared locations of enrichment with somatic cells, which are highly and ubiquitously expressed housekeeping genes, and have lower RNA polymerase II (RNAPII) at the transcription start site (TSS) despite greater nascent transcription. Inhibiting DOT1L increases the efficiency of reprogramming of somatic to induced pluripotent stem cells, enables an ESC-like RNAPII pattern at the TSS, and functionally compensates for enforced RNAPII pausing. DOT1L inhibition increases H3K27 methylation and RNAPII elongation–enhancing histone acetylation without changing the expression of the causal histone-modifying enzymes. Only the maintenance of elevated histone acetylation is essential for enhanced reprogramming and occurs at loci that are depleted for H3K79me2. Thus, DOT1L inhibition promotes the hyperacetylation and hypertranscription pluripotent properties. |
format | Online Article Text |
id | pubmed-10656071 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-106560712023-11-17 DOT1L is a barrier to histone acetylation during reprogramming to pluripotency Wille, Coral K. Zhang, Xiaoya Haws, Spencer A. Denu, John M. Sridharan, Rupa Sci Adv Biomedicine and Life Sciences Embryonic stem cells (ESCs) have transcriptionally permissive chromatin enriched for gene activation–associated histone modifications. A striking exception is DOT1L-mediated H3K79 dimethylation (H3K79me2) that is considered a positive regulator of transcription. We find that ESCs are depleted for H3K79me2 at shared locations of enrichment with somatic cells, which are highly and ubiquitously expressed housekeeping genes, and have lower RNA polymerase II (RNAPII) at the transcription start site (TSS) despite greater nascent transcription. Inhibiting DOT1L increases the efficiency of reprogramming of somatic to induced pluripotent stem cells, enables an ESC-like RNAPII pattern at the TSS, and functionally compensates for enforced RNAPII pausing. DOT1L inhibition increases H3K27 methylation and RNAPII elongation–enhancing histone acetylation without changing the expression of the causal histone-modifying enzymes. Only the maintenance of elevated histone acetylation is essential for enhanced reprogramming and occurs at loci that are depleted for H3K79me2. Thus, DOT1L inhibition promotes the hyperacetylation and hypertranscription pluripotent properties. American Association for the Advancement of Science 2023-11-17 /pmc/articles/PMC10656071/ /pubmed/37976354 http://dx.doi.org/10.1126/sciadv.adf3980 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Wille, Coral K. Zhang, Xiaoya Haws, Spencer A. Denu, John M. Sridharan, Rupa DOT1L is a barrier to histone acetylation during reprogramming to pluripotency |
title | DOT1L is a barrier to histone acetylation during reprogramming to pluripotency |
title_full | DOT1L is a barrier to histone acetylation during reprogramming to pluripotency |
title_fullStr | DOT1L is a barrier to histone acetylation during reprogramming to pluripotency |
title_full_unstemmed | DOT1L is a barrier to histone acetylation during reprogramming to pluripotency |
title_short | DOT1L is a barrier to histone acetylation during reprogramming to pluripotency |
title_sort | dot1l is a barrier to histone acetylation during reprogramming to pluripotency |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10656071/ https://www.ncbi.nlm.nih.gov/pubmed/37976354 http://dx.doi.org/10.1126/sciadv.adf3980 |
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