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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...

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Autores principales: Zemskov, Evgeny A., Gross, Christine M., Aggarwal, Saurabh, Zemskova, Marina A., Wu, Xiaomin, Gu, Chenxin, Wang, Ting, Tang, Haiyang, Black, Stephen M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
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.
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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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