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Progesterone Inhibits the Establishment of Activation-Associated Chromatin During T(H)1 Differentiation

T(H)1-mediated diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA) improve during pregnancy, coinciding with increasing levels of the pregnancy hormone progesterone (P4), highlighting P4 as a potential mediator of this immunomodulation. Here, we performed detailed characterization...

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Autores principales: Rundquist, Olof, Nestor, Colm E., Jenmalm, Maria C., Hellberg, Sandra, Gustafsson, Mika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8848251/
https://www.ncbi.nlm.nih.gov/pubmed/35185927
http://dx.doi.org/10.3389/fimmu.2022.835625
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author Rundquist, Olof
Nestor, Colm E.
Jenmalm, Maria C.
Hellberg, Sandra
Gustafsson, Mika
author_facet Rundquist, Olof
Nestor, Colm E.
Jenmalm, Maria C.
Hellberg, Sandra
Gustafsson, Mika
author_sort Rundquist, Olof
collection PubMed
description T(H)1-mediated diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA) improve during pregnancy, coinciding with increasing levels of the pregnancy hormone progesterone (P4), highlighting P4 as a potential mediator of this immunomodulation. Here, we performed detailed characterization of how P4 affects the chromatin and transcriptomic landscape during early human T(H)1 differentiation, utilizing both ATAC-seq and RNA-seq. Time series analysis of the earlier events (0.5-24 hrs) during T(H)1 differentiation revealed that P4 counteracted many of the changes induced during normal differentiation, mainly by downregulating key regulatory genes and their upstream transcription factors (TFs) involved in the initial T-cell activation. Members of the AP-1 complex such as FOSL1, FOSL2, JUN and JUNB were particularly affected, in both in promoters and in distal regulatory elements. Moreover, the changes induced by P4 were significantly enriched for disease-associated changes related to both MS and RA, revealing several shared upstream TFs, where again JUN was highlighted to be of central importance. Our findings support an immune regulatory role for P4 during pregnancy by impeding T-cell activation, a crucial checkpoint during pregnancy and in T-cell mediated diseases, and a central event prior to T-cell lineage commitment. Indeed, P4 is emerging as a likely candidate involved in disease modulation during pregnancy and further studies evaluating P4 as a potential treatment option are needed.
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spelling pubmed-88482512022-02-17 Progesterone Inhibits the Establishment of Activation-Associated Chromatin During T(H)1 Differentiation Rundquist, Olof Nestor, Colm E. Jenmalm, Maria C. Hellberg, Sandra Gustafsson, Mika Front Immunol Immunology T(H)1-mediated diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA) improve during pregnancy, coinciding with increasing levels of the pregnancy hormone progesterone (P4), highlighting P4 as a potential mediator of this immunomodulation. Here, we performed detailed characterization of how P4 affects the chromatin and transcriptomic landscape during early human T(H)1 differentiation, utilizing both ATAC-seq and RNA-seq. Time series analysis of the earlier events (0.5-24 hrs) during T(H)1 differentiation revealed that P4 counteracted many of the changes induced during normal differentiation, mainly by downregulating key regulatory genes and their upstream transcription factors (TFs) involved in the initial T-cell activation. Members of the AP-1 complex such as FOSL1, FOSL2, JUN and JUNB were particularly affected, in both in promoters and in distal regulatory elements. Moreover, the changes induced by P4 were significantly enriched for disease-associated changes related to both MS and RA, revealing several shared upstream TFs, where again JUN was highlighted to be of central importance. Our findings support an immune regulatory role for P4 during pregnancy by impeding T-cell activation, a crucial checkpoint during pregnancy and in T-cell mediated diseases, and a central event prior to T-cell lineage commitment. Indeed, P4 is emerging as a likely candidate involved in disease modulation during pregnancy and further studies evaluating P4 as a potential treatment option are needed. Frontiers Media S.A. 2022-02-02 /pmc/articles/PMC8848251/ /pubmed/35185927 http://dx.doi.org/10.3389/fimmu.2022.835625 Text en Copyright © 2022 Rundquist, Nestor, Jenmalm, Hellberg and Gustafsson 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
Rundquist, Olof
Nestor, Colm E.
Jenmalm, Maria C.
Hellberg, Sandra
Gustafsson, Mika
Progesterone Inhibits the Establishment of Activation-Associated Chromatin During T(H)1 Differentiation
title Progesterone Inhibits the Establishment of Activation-Associated Chromatin During T(H)1 Differentiation
title_full Progesterone Inhibits the Establishment of Activation-Associated Chromatin During T(H)1 Differentiation
title_fullStr Progesterone Inhibits the Establishment of Activation-Associated Chromatin During T(H)1 Differentiation
title_full_unstemmed Progesterone Inhibits the Establishment of Activation-Associated Chromatin During T(H)1 Differentiation
title_short Progesterone Inhibits the Establishment of Activation-Associated Chromatin During T(H)1 Differentiation
title_sort progesterone inhibits the establishment of activation-associated chromatin during t(h)1 differentiation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8848251/
https://www.ncbi.nlm.nih.gov/pubmed/35185927
http://dx.doi.org/10.3389/fimmu.2022.835625
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