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NF-κB-dependent repression of Sox18 transcription factor requires the epigenetic regulators histone deacetylases 1 and 2 in acute lung injury
In acute lung injury (ALI), the NF-κB-mediated downregulation of Sox18 gene expression leads to the disruption of the pulmonary endothelial barrier. Previous studies have suggested that the action of NF-κB as a transcriptional repressor also requires the action of class I histone deacetylases (HDACs...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9386230/ https://www.ncbi.nlm.nih.gov/pubmed/35991176 http://dx.doi.org/10.3389/fphys.2022.947537 |
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author | Zemskov, Evgeny A. Gross, Christine M. Aggarwal, Saurabh Zemskova, Marina A. Wu, Xiaomin Gu, Chenxin Wang, Ting Tang, Haiyang Black, Stephen M. |
author_facet | Zemskov, Evgeny A. Gross, Christine M. Aggarwal, Saurabh Zemskova, Marina A. Wu, Xiaomin Gu, Chenxin Wang, Ting Tang, Haiyang Black, Stephen M. |
author_sort | Zemskov, Evgeny A. |
collection | PubMed |
description | In acute lung injury (ALI), the NF-κB-mediated downregulation of Sox18 gene expression leads to the disruption of the pulmonary endothelial barrier. Previous studies have suggested that the action of NF-κB as a transcriptional repressor also requires the action of class I histone deacetylases (HDACs). Thus, the purpose of this study was to investigate and further delineate the mechanism of Sox18 repression during lipopolysaccharide (LPS) induced ALI. Using selective inhibitors and specific siRNA-driven depletion of HDACs 1-3 in human lung microvascular endothelial cells (HLMVEC) we were able to demonstrate a critical role for HDACs 1 and 2 in the LPS-mediated repression of Sox18 gene expression and the loss of endothelial monolayer integrity. Moreover, our data demonstrate that HDAC1 associates with a transcription-repressive complex within the NF-κB-binding site of Sox18 promoter. Further, we were able to show that the selective inhibitor of HDAC1, tacedinaline, significantly reduced the endothelial permeability and injury associated with LPS challenge in the mouse lung. Taken together, our data demonstrate, for the first time, that transcription repressors HDACs 1 and 2 are involved in pathological mechanism of ALI and can be considered as therapeutic targets. |
format | Online Article Text |
id | pubmed-9386230 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93862302022-08-19 NF-κB-dependent repression of Sox18 transcription factor requires the epigenetic regulators histone deacetylases 1 and 2 in acute lung injury Zemskov, Evgeny A. Gross, Christine M. Aggarwal, Saurabh Zemskova, Marina A. Wu, Xiaomin Gu, Chenxin Wang, Ting Tang, Haiyang Black, Stephen M. Front Physiol Physiology In acute lung injury (ALI), the NF-κB-mediated downregulation of Sox18 gene expression leads to the disruption of the pulmonary endothelial barrier. Previous studies have suggested that the action of NF-κB as a transcriptional repressor also requires the action of class I histone deacetylases (HDACs). Thus, the purpose of this study was to investigate and further delineate the mechanism of Sox18 repression during lipopolysaccharide (LPS) induced ALI. Using selective inhibitors and specific siRNA-driven depletion of HDACs 1-3 in human lung microvascular endothelial cells (HLMVEC) we were able to demonstrate a critical role for HDACs 1 and 2 in the LPS-mediated repression of Sox18 gene expression and the loss of endothelial monolayer integrity. Moreover, our data demonstrate that HDAC1 associates with a transcription-repressive complex within the NF-κB-binding site of Sox18 promoter. Further, we were able to show that the selective inhibitor of HDAC1, tacedinaline, significantly reduced the endothelial permeability and injury associated with LPS challenge in the mouse lung. Taken together, our data demonstrate, for the first time, that transcription repressors HDACs 1 and 2 are involved in pathological mechanism of ALI and can be considered as therapeutic targets. Frontiers Media S.A. 2022-08-04 /pmc/articles/PMC9386230/ /pubmed/35991176 http://dx.doi.org/10.3389/fphys.2022.947537 Text en Copyright © 2022 Zemskov, Gross, Aggarwal, Zemskova, Wu, Gu, Wang, Tang and Black. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Physiology Zemskov, Evgeny A. Gross, Christine M. Aggarwal, Saurabh Zemskova, Marina A. Wu, Xiaomin Gu, Chenxin Wang, Ting Tang, Haiyang Black, Stephen M. NF-κB-dependent repression of Sox18 transcription factor requires the epigenetic regulators histone deacetylases 1 and 2 in acute lung injury |
title | NF-κB-dependent repression of Sox18 transcription factor requires the epigenetic regulators histone deacetylases 1 and 2 in acute lung injury |
title_full | NF-κB-dependent repression of Sox18 transcription factor requires the epigenetic regulators histone deacetylases 1 and 2 in acute lung injury |
title_fullStr | NF-κB-dependent repression of Sox18 transcription factor requires the epigenetic regulators histone deacetylases 1 and 2 in acute lung injury |
title_full_unstemmed | NF-κB-dependent repression of Sox18 transcription factor requires the epigenetic regulators histone deacetylases 1 and 2 in acute lung injury |
title_short | NF-κB-dependent repression of Sox18 transcription factor requires the epigenetic regulators histone deacetylases 1 and 2 in acute lung injury |
title_sort | nf-κb-dependent repression of sox18 transcription factor requires the epigenetic regulators histone deacetylases 1 and 2 in acute lung injury |
topic | Physiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9386230/ https://www.ncbi.nlm.nih.gov/pubmed/35991176 http://dx.doi.org/10.3389/fphys.2022.947537 |
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