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CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors
Progenitors in epithelial tissues, such as human skin epidermis, continuously make fate decisions between self-renewal and differentiation. Here we show that the Super Elongation Complex (SEC) controls progenitor fate decisions by directly suppressing a group of “rapid response” genes, which feature...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9338292/ https://www.ncbi.nlm.nih.gov/pubmed/35906225 http://dx.doi.org/10.1038/s41467-022-32098-2 |
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author | Lloyd, Sarah M. Leon, Daniel B. Brady, Mari O. Rodriguez, Deborah McReynolds, Madison P. Kweon, Junghun Neely, Amy E. Blumensaadt, Laura A. Ho, Patric J. Bao, Xiaomin |
author_facet | Lloyd, Sarah M. Leon, Daniel B. Brady, Mari O. Rodriguez, Deborah McReynolds, Madison P. Kweon, Junghun Neely, Amy E. Blumensaadt, Laura A. Ho, Patric J. Bao, Xiaomin |
author_sort | Lloyd, Sarah M. |
collection | PubMed |
description | Progenitors in epithelial tissues, such as human skin epidermis, continuously make fate decisions between self-renewal and differentiation. Here we show that the Super Elongation Complex (SEC) controls progenitor fate decisions by directly suppressing a group of “rapid response” genes, which feature high enrichment of paused Pol II in the progenitor state and robust Pol II elongation in differentiation. SEC’s repressive role is dependent on the AFF1 scaffold, but not AFF4. In the progenitor state, AFF1-SEC associates with the HEXIM1-containing inactive CDK9 to suppress these rapid-response genes. A key rapid-response SEC target is ATF3, which promotes the upregulation of differentiation-activating transcription factors (GRHL3, OVOL1, PRDM1, ZNF750) to advance terminal differentiation. SEC peptidomimetic inhibitors or PKC signaling activates CDK9 and rapidly induces these transcription factors within hours in keratinocytes. Thus, our data suggest that the activity switch of SEC-associated CDK9 underlies the initial processes bifurcating progenitor fates between self-renewal and differentiation. |
format | Online Article Text |
id | pubmed-9338292 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-93382922022-07-31 CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors Lloyd, Sarah M. Leon, Daniel B. Brady, Mari O. Rodriguez, Deborah McReynolds, Madison P. Kweon, Junghun Neely, Amy E. Blumensaadt, Laura A. Ho, Patric J. Bao, Xiaomin Nat Commun Article Progenitors in epithelial tissues, such as human skin epidermis, continuously make fate decisions between self-renewal and differentiation. Here we show that the Super Elongation Complex (SEC) controls progenitor fate decisions by directly suppressing a group of “rapid response” genes, which feature high enrichment of paused Pol II in the progenitor state and robust Pol II elongation in differentiation. SEC’s repressive role is dependent on the AFF1 scaffold, but not AFF4. In the progenitor state, AFF1-SEC associates with the HEXIM1-containing inactive CDK9 to suppress these rapid-response genes. A key rapid-response SEC target is ATF3, which promotes the upregulation of differentiation-activating transcription factors (GRHL3, OVOL1, PRDM1, ZNF750) to advance terminal differentiation. SEC peptidomimetic inhibitors or PKC signaling activates CDK9 and rapidly induces these transcription factors within hours in keratinocytes. Thus, our data suggest that the activity switch of SEC-associated CDK9 underlies the initial processes bifurcating progenitor fates between self-renewal and differentiation. Nature Publishing Group UK 2022-07-29 /pmc/articles/PMC9338292/ /pubmed/35906225 http://dx.doi.org/10.1038/s41467-022-32098-2 Text en © The Author(s) 2022 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 Lloyd, Sarah M. Leon, Daniel B. Brady, Mari O. Rodriguez, Deborah McReynolds, Madison P. Kweon, Junghun Neely, Amy E. Blumensaadt, Laura A. Ho, Patric J. Bao, Xiaomin CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors |
title | CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors |
title_full | CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors |
title_fullStr | CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors |
title_full_unstemmed | CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors |
title_short | CDK9 activity switch associated with AFF1 and HEXIM1 controls differentiation initiation from epidermal progenitors |
title_sort | cdk9 activity switch associated with aff1 and hexim1 controls differentiation initiation from epidermal progenitors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9338292/ https://www.ncbi.nlm.nih.gov/pubmed/35906225 http://dx.doi.org/10.1038/s41467-022-32098-2 |
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