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Chromatin accessibility dynamics dictate renal tubular epithelial cell response to injury

Renal tubular epithelial cells (TECs) can initiate an adaptive response to completely recover from mild acute kidney injury (AKI), whereas severe injury often leads to persistence of maladaptive repair and progression to kidney fibrosis. Through profiling of active DNA regulatory elements by ATAC-se...

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Autores principales: Cao, Xinyi, Wang, Jiuchen, Zhang, Tianye, Liu, Zhiheng, Liu, Lijun, Chen, Ying, Li, Zehua, Zhao, Youlu, Yu, Qi, Liu, Tong, Nie, Jing, Niu, Yuanjie, Chen, Yupeng, Yang, Li, Zhang, Lirong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9705299/
https://www.ncbi.nlm.nih.gov/pubmed/36443310
http://dx.doi.org/10.1038/s41467-022-34854-w
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author Cao, Xinyi
Wang, Jiuchen
Zhang, Tianye
Liu, Zhiheng
Liu, Lijun
Chen, Ying
Li, Zehua
Zhao, Youlu
Yu, Qi
Liu, Tong
Nie, Jing
Niu, Yuanjie
Chen, Yupeng
Yang, Li
Zhang, Lirong
author_facet Cao, Xinyi
Wang, Jiuchen
Zhang, Tianye
Liu, Zhiheng
Liu, Lijun
Chen, Ying
Li, Zehua
Zhao, Youlu
Yu, Qi
Liu, Tong
Nie, Jing
Niu, Yuanjie
Chen, Yupeng
Yang, Li
Zhang, Lirong
author_sort Cao, Xinyi
collection PubMed
description Renal tubular epithelial cells (TECs) can initiate an adaptive response to completely recover from mild acute kidney injury (AKI), whereas severe injury often leads to persistence of maladaptive repair and progression to kidney fibrosis. Through profiling of active DNA regulatory elements by ATAC-seq, we reveal widespread, dynamic changes in the chromatin accessibility of TECs after ischemia–reperfusion injury. We show that injury-specific domains of regulatory chromatin become accessible prior to gene activation, creating poised chromatin states to activate the consequent gene expression program and injury response. We further identify RXRα as a key transcription factor in promoting adaptive repair. Activation of RXRα by bexarotene, an FDA-approved RXRα agonist, restores the chromatin state and gene expression program to protect TECs against severe kidney injury. Together, our findings elucidate a chromatin-mediated mechanism underlying differential responses of TECs to varying injuries and identify RXRα as a therapeutic target of acute kidney injury.
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spelling pubmed-97052992022-11-30 Chromatin accessibility dynamics dictate renal tubular epithelial cell response to injury Cao, Xinyi Wang, Jiuchen Zhang, Tianye Liu, Zhiheng Liu, Lijun Chen, Ying Li, Zehua Zhao, Youlu Yu, Qi Liu, Tong Nie, Jing Niu, Yuanjie Chen, Yupeng Yang, Li Zhang, Lirong Nat Commun Article Renal tubular epithelial cells (TECs) can initiate an adaptive response to completely recover from mild acute kidney injury (AKI), whereas severe injury often leads to persistence of maladaptive repair and progression to kidney fibrosis. Through profiling of active DNA regulatory elements by ATAC-seq, we reveal widespread, dynamic changes in the chromatin accessibility of TECs after ischemia–reperfusion injury. We show that injury-specific domains of regulatory chromatin become accessible prior to gene activation, creating poised chromatin states to activate the consequent gene expression program and injury response. We further identify RXRα as a key transcription factor in promoting adaptive repair. Activation of RXRα by bexarotene, an FDA-approved RXRα agonist, restores the chromatin state and gene expression program to protect TECs against severe kidney injury. Together, our findings elucidate a chromatin-mediated mechanism underlying differential responses of TECs to varying injuries and identify RXRα as a therapeutic target of acute kidney injury. Nature Publishing Group UK 2022-11-28 /pmc/articles/PMC9705299/ /pubmed/36443310 http://dx.doi.org/10.1038/s41467-022-34854-w 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
Cao, Xinyi
Wang, Jiuchen
Zhang, Tianye
Liu, Zhiheng
Liu, Lijun
Chen, Ying
Li, Zehua
Zhao, Youlu
Yu, Qi
Liu, Tong
Nie, Jing
Niu, Yuanjie
Chen, Yupeng
Yang, Li
Zhang, Lirong
Chromatin accessibility dynamics dictate renal tubular epithelial cell response to injury
title Chromatin accessibility dynamics dictate renal tubular epithelial cell response to injury
title_full Chromatin accessibility dynamics dictate renal tubular epithelial cell response to injury
title_fullStr Chromatin accessibility dynamics dictate renal tubular epithelial cell response to injury
title_full_unstemmed Chromatin accessibility dynamics dictate renal tubular epithelial cell response to injury
title_short Chromatin accessibility dynamics dictate renal tubular epithelial cell response to injury
title_sort chromatin accessibility dynamics dictate renal tubular epithelial cell response to injury
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9705299/
https://www.ncbi.nlm.nih.gov/pubmed/36443310
http://dx.doi.org/10.1038/s41467-022-34854-w
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