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The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates
During development, progenitors simultaneously activate one lineage while silencing another, a feature highly regulated in adult stem cells but derailed in cancers. Equipped to bind cognate motifs in closed chromatin, pioneer factors operate at these crossroads, but how they perform fate switching r...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10415178/ https://www.ncbi.nlm.nih.gov/pubmed/37488435 http://dx.doi.org/10.1038/s41556-023-01184-y |
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author | Yang, Yihao Gomez, Nicholas Infarinato, Nicole Adam, Rene C. Sribour, Megan Baek, Inwha Laurin, Mélanie Fuchs, Elaine |
author_facet | Yang, Yihao Gomez, Nicholas Infarinato, Nicole Adam, Rene C. Sribour, Megan Baek, Inwha Laurin, Mélanie Fuchs, Elaine |
author_sort | Yang, Yihao |
collection | PubMed |
description | During development, progenitors simultaneously activate one lineage while silencing another, a feature highly regulated in adult stem cells but derailed in cancers. Equipped to bind cognate motifs in closed chromatin, pioneer factors operate at these crossroads, but how they perform fate switching remains elusive. Here we tackle this question with SOX9, a master regulator that diverts embryonic epidermal stem cells (EpdSCs) into becoming hair follicle stem cells. By engineering mice to re-activate SOX9 in adult EpdSCs, we trigger fate switching. Combining epigenetic, proteomic and functional analyses, we interrogate the ensuing chromatin and transcriptional dynamics, slowed temporally by the mature EpdSC niche microenvironment. We show that as SOX9 binds and opens key hair follicle enhancers de novo in EpdSCs, it simultaneously recruits co-factors away from epidermal enhancers, which are silenced. Unhinged from its normal regulation, sustained SOX9 subsequently activates oncogenic transcriptional regulators that chart the path to cancers typified by constitutive SOX9 expression. |
format | Online Article Text |
id | pubmed-10415178 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-104151782023-08-12 The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates Yang, Yihao Gomez, Nicholas Infarinato, Nicole Adam, Rene C. Sribour, Megan Baek, Inwha Laurin, Mélanie Fuchs, Elaine Nat Cell Biol Article During development, progenitors simultaneously activate one lineage while silencing another, a feature highly regulated in adult stem cells but derailed in cancers. Equipped to bind cognate motifs in closed chromatin, pioneer factors operate at these crossroads, but how they perform fate switching remains elusive. Here we tackle this question with SOX9, a master regulator that diverts embryonic epidermal stem cells (EpdSCs) into becoming hair follicle stem cells. By engineering mice to re-activate SOX9 in adult EpdSCs, we trigger fate switching. Combining epigenetic, proteomic and functional analyses, we interrogate the ensuing chromatin and transcriptional dynamics, slowed temporally by the mature EpdSC niche microenvironment. We show that as SOX9 binds and opens key hair follicle enhancers de novo in EpdSCs, it simultaneously recruits co-factors away from epidermal enhancers, which are silenced. Unhinged from its normal regulation, sustained SOX9 subsequently activates oncogenic transcriptional regulators that chart the path to cancers typified by constitutive SOX9 expression. Nature Publishing Group UK 2023-07-24 2023 /pmc/articles/PMC10415178/ /pubmed/37488435 http://dx.doi.org/10.1038/s41556-023-01184-y Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Yang, Yihao Gomez, Nicholas Infarinato, Nicole Adam, Rene C. Sribour, Megan Baek, Inwha Laurin, Mélanie Fuchs, Elaine The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates |
title | The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates |
title_full | The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates |
title_fullStr | The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates |
title_full_unstemmed | The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates |
title_short | The pioneer factor SOX9 competes for epigenetic factors to switch stem cell fates |
title_sort | pioneer factor sox9 competes for epigenetic factors to switch stem cell fates |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10415178/ https://www.ncbi.nlm.nih.gov/pubmed/37488435 http://dx.doi.org/10.1038/s41556-023-01184-y |
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