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Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation

Naive CD4(+) T lymphocytes differentiate into different effector types, including helper and regulatory cells (Th and Treg, respectively). Heritable gene expression programs that define these effector types are established during differentiation, but little is known about the epigenetic mechanisms t...

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Autores principales: Gehrmann, Ulf, Burbage, Marianne, Zueva, Elina, Goudot, Christel, Esnault, Cyril, Ye, Mengliang, Carpier, Jean-Marie, Burgdorf, Nina, Hoyler, Thomas, Suarez, Guadalupe, Joannas, Leonel, Heurtebise-Chrétien, Sandrine, Durand, Sylvère, Panes, Rébecca, Bellemare-Pelletier, Angélique, Sáez, Pablo J., Aprahamian, Fanny, Lefevre, Deborah, Adoue, Veronique, Zine El Aabidine, Amal, Muhammad Ahmad, Maqbool, Hivroz, Claire, Joffre, Olivier, Cammas, Florence, Kroemer, Guido, Gagnon, Etienne, Andrau, Jean-Christophe, Amigorena, Sebastian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925996/
https://www.ncbi.nlm.nih.gov/pubmed/31776254
http://dx.doi.org/10.1073/pnas.1901639116
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author Gehrmann, Ulf
Burbage, Marianne
Zueva, Elina
Goudot, Christel
Esnault, Cyril
Ye, Mengliang
Carpier, Jean-Marie
Burgdorf, Nina
Hoyler, Thomas
Suarez, Guadalupe
Joannas, Leonel
Heurtebise-Chrétien, Sandrine
Durand, Sylvère
Panes, Rébecca
Bellemare-Pelletier, Angélique
Sáez, Pablo J.
Aprahamian, Fanny
Lefevre, Deborah
Adoue, Veronique
Zine El Aabidine, Amal
Muhammad Ahmad, Maqbool
Hivroz, Claire
Joffre, Olivier
Cammas, Florence
Kroemer, Guido
Gagnon, Etienne
Andrau, Jean-Christophe
Amigorena, Sebastian
author_facet Gehrmann, Ulf
Burbage, Marianne
Zueva, Elina
Goudot, Christel
Esnault, Cyril
Ye, Mengliang
Carpier, Jean-Marie
Burgdorf, Nina
Hoyler, Thomas
Suarez, Guadalupe
Joannas, Leonel
Heurtebise-Chrétien, Sandrine
Durand, Sylvère
Panes, Rébecca
Bellemare-Pelletier, Angélique
Sáez, Pablo J.
Aprahamian, Fanny
Lefevre, Deborah
Adoue, Veronique
Zine El Aabidine, Amal
Muhammad Ahmad, Maqbool
Hivroz, Claire
Joffre, Olivier
Cammas, Florence
Kroemer, Guido
Gagnon, Etienne
Andrau, Jean-Christophe
Amigorena, Sebastian
author_sort Gehrmann, Ulf
collection PubMed
description Naive CD4(+) T lymphocytes differentiate into different effector types, including helper and regulatory cells (Th and Treg, respectively). Heritable gene expression programs that define these effector types are established during differentiation, but little is known about the epigenetic mechanisms that install and maintain these programs. Here, we use mice defective for different components of heterochromatin-dependent gene silencing to investigate the epigenetic control of CD4(+) T cell plasticity. We show that, upon T cell receptor (TCR) engagement, naive and regulatory T cells defective for TRIM28 (an epigenetic adaptor for histone binding modules) or for heterochromatin protein 1 β and γ isoforms (HP1β/γ, 2 histone-binding factors involved in gene silencing) fail to effectively signal through the PI3K–AKT–mTOR axis and switch to glycolysis. While differentiation of naive TRIM28(−/−) T cells into cytokine-producing effector T cells is impaired, resulting in reduced induction of autoimmune colitis, TRIM28(−/−) regulatory T cells also fail to expand in vivo and to suppress autoimmunity effectively. Using a combination of transcriptome and chromatin immunoprecipitation-sequencing (ChIP-seq) analyses for H3K9me3, H3K9Ac, and RNA polymerase II, we show that reduced effector differentiation correlates with impaired transcriptional silencing at distal regulatory regions of a defined set of Treg-associated genes, including, for example, NRP1 or Snai3. We conclude that TRIM28 and HP1β/γ control metabolic reprograming through epigenetic silencing of a defined set of Treg-characteristic genes, thus allowing effective T cell expansion and differentiation into helper and regulatory phenotypes.
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spelling pubmed-69259962019-12-23 Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation Gehrmann, Ulf Burbage, Marianne Zueva, Elina Goudot, Christel Esnault, Cyril Ye, Mengliang Carpier, Jean-Marie Burgdorf, Nina Hoyler, Thomas Suarez, Guadalupe Joannas, Leonel Heurtebise-Chrétien, Sandrine Durand, Sylvère Panes, Rébecca Bellemare-Pelletier, Angélique Sáez, Pablo J. Aprahamian, Fanny Lefevre, Deborah Adoue, Veronique Zine El Aabidine, Amal Muhammad Ahmad, Maqbool Hivroz, Claire Joffre, Olivier Cammas, Florence Kroemer, Guido Gagnon, Etienne Andrau, Jean-Christophe Amigorena, Sebastian Proc Natl Acad Sci U S A PNAS Plus Naive CD4(+) T lymphocytes differentiate into different effector types, including helper and regulatory cells (Th and Treg, respectively). Heritable gene expression programs that define these effector types are established during differentiation, but little is known about the epigenetic mechanisms that install and maintain these programs. Here, we use mice defective for different components of heterochromatin-dependent gene silencing to investigate the epigenetic control of CD4(+) T cell plasticity. We show that, upon T cell receptor (TCR) engagement, naive and regulatory T cells defective for TRIM28 (an epigenetic adaptor for histone binding modules) or for heterochromatin protein 1 β and γ isoforms (HP1β/γ, 2 histone-binding factors involved in gene silencing) fail to effectively signal through the PI3K–AKT–mTOR axis and switch to glycolysis. While differentiation of naive TRIM28(−/−) T cells into cytokine-producing effector T cells is impaired, resulting in reduced induction of autoimmune colitis, TRIM28(−/−) regulatory T cells also fail to expand in vivo and to suppress autoimmunity effectively. Using a combination of transcriptome and chromatin immunoprecipitation-sequencing (ChIP-seq) analyses for H3K9me3, H3K9Ac, and RNA polymerase II, we show that reduced effector differentiation correlates with impaired transcriptional silencing at distal regulatory regions of a defined set of Treg-associated genes, including, for example, NRP1 or Snai3. We conclude that TRIM28 and HP1β/γ control metabolic reprograming through epigenetic silencing of a defined set of Treg-characteristic genes, thus allowing effective T cell expansion and differentiation into helper and regulatory phenotypes. National Academy of Sciences 2019-12-17 2019-11-27 /pmc/articles/PMC6925996/ /pubmed/31776254 http://dx.doi.org/10.1073/pnas.1901639116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Gehrmann, Ulf
Burbage, Marianne
Zueva, Elina
Goudot, Christel
Esnault, Cyril
Ye, Mengliang
Carpier, Jean-Marie
Burgdorf, Nina
Hoyler, Thomas
Suarez, Guadalupe
Joannas, Leonel
Heurtebise-Chrétien, Sandrine
Durand, Sylvère
Panes, Rébecca
Bellemare-Pelletier, Angélique
Sáez, Pablo J.
Aprahamian, Fanny
Lefevre, Deborah
Adoue, Veronique
Zine El Aabidine, Amal
Muhammad Ahmad, Maqbool
Hivroz, Claire
Joffre, Olivier
Cammas, Florence
Kroemer, Guido
Gagnon, Etienne
Andrau, Jean-Christophe
Amigorena, Sebastian
Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation
title Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation
title_full Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation
title_fullStr Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation
title_full_unstemmed Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation
title_short Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation
title_sort critical role for trim28 and hp1β/γ in the epigenetic control of t cell metabolic reprograming and effector differentiation
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925996/
https://www.ncbi.nlm.nih.gov/pubmed/31776254
http://dx.doi.org/10.1073/pnas.1901639116
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