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H3K27 demethylase KDM6B aggravates ischemic brain injury through demethylation of IRF4 and Notch2-dependent SOX9 activation

Lysine demethylase 6B (KDM6B) is a histone H3 lysine 27 (H3K27) demethylase that serves as a key mediator of gene transcription. Although KDM6B has been reported to modulate neuroinflammation after ischemic stroke, its role in ischemic brain injury is yet to be well elucidated. Therefore, this study...

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Autores principales: Chang, Lisha, An, Zhaowang, Zhang, Jiang, Zhou, Fuling, Wang, Dali, Liu, Jian, Zhang, Yunhe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076647/
https://www.ncbi.nlm.nih.gov/pubmed/33981480
http://dx.doi.org/10.1016/j.omtn.2021.01.021
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author Chang, Lisha
An, Zhaowang
Zhang, Jiang
Zhou, Fuling
Wang, Dali
Liu, Jian
Zhang, Yunhe
author_facet Chang, Lisha
An, Zhaowang
Zhang, Jiang
Zhou, Fuling
Wang, Dali
Liu, Jian
Zhang, Yunhe
author_sort Chang, Lisha
collection PubMed
description Lysine demethylase 6B (KDM6B) is a histone H3 lysine 27 (H3K27) demethylase that serves as a key mediator of gene transcription. Although KDM6B has been reported to modulate neuroinflammation after ischemic stroke, its role in ischemic brain injury is yet to be well elucidated. Therefore, this study aimed to thoroughly demonstrate the molecular mechanism underlying the effect of KDM6B on neurological function and astrocyte response in post-ischemic brain injury. Middle cerebral artery occlusion/reperfusion (MCAO) mouse models were constructed, while the oxygen-glucose deprivation/reperfusion (OGD/R) model was developed in astrocytes to mimic injury conditions. KDM6B was upregulated post-MCAO in mice and in astrocytes following the induction of OGD/R. Silencing of KDM6B resulted in suppressed neurological deficit, reduced cerebral infarction volume, attenuated neuronal cell apoptosis, and disrupted inflammation. Dual-luciferase reporter gene and chromatin immunoprecipitation-quantitative polymerase chain reaction assays revealed that KDM6B inhibited H3K27 trimethylation in the interferon regulatory factor 4 (IRF4) promoter region, resulting in the upregulation of IRF4 expression, which in turn bound to the Notch2 promoter region to induce its downstream factor SRY-related high-mobility group box 9 (SOX9). SOX9 knockdown reversed the effects of KDM6B overexpression on ischemia-triggered brain damage. Based on these findings, we concluded that KDM6B-mediated demethylation of IRF4 contributes to aggravation of ischemic brain injury through SOX9 activation.
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spelling pubmed-80766472021-05-11 H3K27 demethylase KDM6B aggravates ischemic brain injury through demethylation of IRF4 and Notch2-dependent SOX9 activation Chang, Lisha An, Zhaowang Zhang, Jiang Zhou, Fuling Wang, Dali Liu, Jian Zhang, Yunhe Mol Ther Nucleic Acids Original Article Lysine demethylase 6B (KDM6B) is a histone H3 lysine 27 (H3K27) demethylase that serves as a key mediator of gene transcription. Although KDM6B has been reported to modulate neuroinflammation after ischemic stroke, its role in ischemic brain injury is yet to be well elucidated. Therefore, this study aimed to thoroughly demonstrate the molecular mechanism underlying the effect of KDM6B on neurological function and astrocyte response in post-ischemic brain injury. Middle cerebral artery occlusion/reperfusion (MCAO) mouse models were constructed, while the oxygen-glucose deprivation/reperfusion (OGD/R) model was developed in astrocytes to mimic injury conditions. KDM6B was upregulated post-MCAO in mice and in astrocytes following the induction of OGD/R. Silencing of KDM6B resulted in suppressed neurological deficit, reduced cerebral infarction volume, attenuated neuronal cell apoptosis, and disrupted inflammation. Dual-luciferase reporter gene and chromatin immunoprecipitation-quantitative polymerase chain reaction assays revealed that KDM6B inhibited H3K27 trimethylation in the interferon regulatory factor 4 (IRF4) promoter region, resulting in the upregulation of IRF4 expression, which in turn bound to the Notch2 promoter region to induce its downstream factor SRY-related high-mobility group box 9 (SOX9). SOX9 knockdown reversed the effects of KDM6B overexpression on ischemia-triggered brain damage. Based on these findings, we concluded that KDM6B-mediated demethylation of IRF4 contributes to aggravation of ischemic brain injury through SOX9 activation. American Society of Gene & Cell Therapy 2021-01-26 /pmc/articles/PMC8076647/ /pubmed/33981480 http://dx.doi.org/10.1016/j.omtn.2021.01.021 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Chang, Lisha
An, Zhaowang
Zhang, Jiang
Zhou, Fuling
Wang, Dali
Liu, Jian
Zhang, Yunhe
H3K27 demethylase KDM6B aggravates ischemic brain injury through demethylation of IRF4 and Notch2-dependent SOX9 activation
title H3K27 demethylase KDM6B aggravates ischemic brain injury through demethylation of IRF4 and Notch2-dependent SOX9 activation
title_full H3K27 demethylase KDM6B aggravates ischemic brain injury through demethylation of IRF4 and Notch2-dependent SOX9 activation
title_fullStr H3K27 demethylase KDM6B aggravates ischemic brain injury through demethylation of IRF4 and Notch2-dependent SOX9 activation
title_full_unstemmed H3K27 demethylase KDM6B aggravates ischemic brain injury through demethylation of IRF4 and Notch2-dependent SOX9 activation
title_short H3K27 demethylase KDM6B aggravates ischemic brain injury through demethylation of IRF4 and Notch2-dependent SOX9 activation
title_sort h3k27 demethylase kdm6b aggravates ischemic brain injury through demethylation of irf4 and notch2-dependent sox9 activation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076647/
https://www.ncbi.nlm.nih.gov/pubmed/33981480
http://dx.doi.org/10.1016/j.omtn.2021.01.021
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