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Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2019

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

Elina Zueva
  • Fonction : Auteur
Mengliang Ye
  • Fonction : Auteur
Véronique Adoue
  • Fonction : Auteur
  • PersonId : 1058526
Claire Hivroz
Olivier Joffre

Résumé

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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Dates et versions

hal-02369616 , version 1 (15-12-2020)

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Ulf Gehrmann, Marianne Burbage, Elina Zueva, Christel Goudot, Cyril Esnault, et al.. Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation. Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (51), pp.25839-25849. ⟨10.1073/pnas.1901639116⟩. ⟨hal-02369616⟩
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