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Inhibiting KDM6A Demethylase Represses Long Non-Coding RNA Hotairm1 Transcription in MDSC During Sepsis

Myeloid-derived suppressor cells (MDSCs) prolong sepsis by promoting immunosuppression. We reported that sepsis MDSC development requires long non-coding RNA Hotairm1 interactions with S100A9. Using a mouse model that simulates the immunobiology of sepsis, we find that histone demethylase KDM6A prom...

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Autores principales: Bah, Isatou, Youssef, Dima, Yao, Zhi Q., McCall, Charles E., El Gazzar, Mohamed
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851568/
https://www.ncbi.nlm.nih.gov/pubmed/35185915
http://dx.doi.org/10.3389/fimmu.2022.823660
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author Bah, Isatou
Youssef, Dima
Yao, Zhi Q.
McCall, Charles E.
El Gazzar, Mohamed
author_facet Bah, Isatou
Youssef, Dima
Yao, Zhi Q.
McCall, Charles E.
El Gazzar, Mohamed
author_sort Bah, Isatou
collection PubMed
description Myeloid-derived suppressor cells (MDSCs) prolong sepsis by promoting immunosuppression. We reported that sepsis MDSC development requires long non-coding RNA Hotairm1 interactions with S100A9. Using a mouse model that simulates the immunobiology of sepsis, we find that histone demethylase KDM6A promotes Hotairm1 transcription by demethylating transcription repression H3K27me3 histone mark. We show that chemical targeting of KDM6A by GSK-J4 represses Hotairm1 transcription, which coincides with decreases in transcription activation H3K4me3 histone mark and transcription factor PU.1 binding to the Hotairm1 promoter. We further show that immunosuppressive IL-10 cytokine promotes KDM6A binding at the Hotairm1 promoter. IL-10 knockdown repletes H3K27me3 and reduces Hotairm1 transcription. GSK-J4 treatment also relocalizes nuclear S100A9 protein to the cytosol. To support translation to human sepsis, we demonstrate that inhibiting H3K27me3 demethylation by KDM6A ex vivo in MDSCs from patients with protracted sepsis decreases Hotairm1 transcription. These findings suggest that epigenetic targeting of MDSCs in human sepsis might resolve post-sepsis immunosuppression and improve sepsis survival.
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spelling pubmed-88515682022-02-18 Inhibiting KDM6A Demethylase Represses Long Non-Coding RNA Hotairm1 Transcription in MDSC During Sepsis Bah, Isatou Youssef, Dima Yao, Zhi Q. McCall, Charles E. El Gazzar, Mohamed Front Immunol Immunology Myeloid-derived suppressor cells (MDSCs) prolong sepsis by promoting immunosuppression. We reported that sepsis MDSC development requires long non-coding RNA Hotairm1 interactions with S100A9. Using a mouse model that simulates the immunobiology of sepsis, we find that histone demethylase KDM6A promotes Hotairm1 transcription by demethylating transcription repression H3K27me3 histone mark. We show that chemical targeting of KDM6A by GSK-J4 represses Hotairm1 transcription, which coincides with decreases in transcription activation H3K4me3 histone mark and transcription factor PU.1 binding to the Hotairm1 promoter. We further show that immunosuppressive IL-10 cytokine promotes KDM6A binding at the Hotairm1 promoter. IL-10 knockdown repletes H3K27me3 and reduces Hotairm1 transcription. GSK-J4 treatment also relocalizes nuclear S100A9 protein to the cytosol. To support translation to human sepsis, we demonstrate that inhibiting H3K27me3 demethylation by KDM6A ex vivo in MDSCs from patients with protracted sepsis decreases Hotairm1 transcription. These findings suggest that epigenetic targeting of MDSCs in human sepsis might resolve post-sepsis immunosuppression and improve sepsis survival. Frontiers Media S.A. 2022-01-28 /pmc/articles/PMC8851568/ /pubmed/35185915 http://dx.doi.org/10.3389/fimmu.2022.823660 Text en Copyright © 2022 Bah, Youssef, Yao, McCall and El Gazzar 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 Immunology
Bah, Isatou
Youssef, Dima
Yao, Zhi Q.
McCall, Charles E.
El Gazzar, Mohamed
Inhibiting KDM6A Demethylase Represses Long Non-Coding RNA Hotairm1 Transcription in MDSC During Sepsis
title Inhibiting KDM6A Demethylase Represses Long Non-Coding RNA Hotairm1 Transcription in MDSC During Sepsis
title_full Inhibiting KDM6A Demethylase Represses Long Non-Coding RNA Hotairm1 Transcription in MDSC During Sepsis
title_fullStr Inhibiting KDM6A Demethylase Represses Long Non-Coding RNA Hotairm1 Transcription in MDSC During Sepsis
title_full_unstemmed Inhibiting KDM6A Demethylase Represses Long Non-Coding RNA Hotairm1 Transcription in MDSC During Sepsis
title_short Inhibiting KDM6A Demethylase Represses Long Non-Coding RNA Hotairm1 Transcription in MDSC During Sepsis
title_sort inhibiting kdm6a demethylase represses long non-coding rna hotairm1 transcription in mdsc during sepsis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851568/
https://www.ncbi.nlm.nih.gov/pubmed/35185915
http://dx.doi.org/10.3389/fimmu.2022.823660
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