Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation
| العنوان: | Critical role for TRIM28 and HP1β/γ in the epigenetic control of T cell metabolic reprograming and effector differentiation |
|---|---|
| المؤلفون: | Marianne Burbage, Pablo J. Sáez, Deborah Lefevre, Thomas Hoyler, Amal Zine El Aabidine, Rébecca Panes, Guadalupe Suarez, Christel Goudot, Sebastian Amigorena, Jean-Marie Carpier, Mengliang Ye, Fanny Aprahamian, Claire Hivroz, Florence Cammas, Olivier Joffre, Véronique Adoue, Elina Zueva, Jean-Christophe Andrau, Angelique Bellemare-Pelletier, Sylvère Durand, Leonel Joannas, Etienne Gagnon, Maqbool Muhammad Ahmad, Guido Kroemer, Cyril Esnault, Ulf Gehrmann, Sandrine Heurtebise-Chrétien, Nina Burgdorf |
| المساهمون: | Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), AstraZeneca, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Métabolisme, Cancer et Immunité (CRC - UMR_S 1138), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Montréal (UdeM), Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Karolinska University Hospital [Stockholm], ANR-10-BLAN-1326,chromaTin,Dynamique de la chromatine au cours de l'activation des lympohocytes T: role de HP1(2010), ANR-11-LABX-0043,DCBIOL,Biologie des cellules dendritiques(2011), ANR-10-IDEX-0001,PSL,Paris Sciences et Lettres(2010), ANR-14-CE14-0021,EpiTreg,Régulation épigénétique du développement et de l'activité des lymphocytes T (régulateurs) par HP1 et son interactome(2014), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-11-LABX-0038,CelTisPhyBio,Des cellules aux tissus: au croisement de la Physique et de la Biologie(2011), ANR-16-CE18-0023,Healskin,Matrices pour la régénération et la cicatrisation cutanée(2016), ANR-10-EQPX-0003,ICGex,Equipement de biologie intégrative du cancer pour une médecine personnalisée(2010), ANR-11-LABX-0044,DEEP,Développement, Epigénèse, Epigénétique et potentiel de vie(2011), European Project: 340046,EC:FP7:ERC,ERC-2013-ADG,DCBIOX(2014) |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2019, 116 (51), pp.25839-25849. ⟨10.1073/pnas.1901639116⟩ Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (51), pp.25839-25849. ⟨10.1073/pnas.1901639116⟩ |
| بيانات النشر: | HAL CCSD, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | CD4-Positive T-Lymphocytes, Chromosomal Proteins, Non-Histone, MESH: Cellular Reprogramming / genetics, T-Lymphocytes, MESH: Cellular Reprogramming / physiology, [SDV]Life Sciences [q-bio], Cell Plasticity, MESH: Chromobox Protein Homolog 5, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Tripartite Motif-Containing Protein 28, T-Lymphocytes, Regulatory, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Epigenesis, Genetic, Histones, immunology, Mice, Phosphatidylinositol 3-Kinases, Immunology and Inflammation, 0302 clinical medicine, MESH: Animals, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, 0303 health sciences, Multidisciplinary, Effector, autoimmunity, Cell Differentiation, MESH: DNA-Binding Proteins / metabolism, Biological Sciences, MESH: Cell Differentiation / physiology, Cellular Reprogramming, MESH: Gene Expression Regulation, MESH: Cell Differentiation / genetics, Chromatin, Cell biology, DNA-Binding Proteins, medicine.anatomical_structure, PNAS Plus, Regulatory sequence, 030220 oncology & carcinogenesis, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Chromosomal Proteins, Non-Histone / metabolism, MESH: Epigenesis, Genetic / physiology, MESH: Cell Plasticity / physiology, Colon, T cell, Receptors, Antigen, T-Cell, T cells, Biology, 03 medical and health sciences, MESH: CD4-Positive T-Lymphocytes / metabolism, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Animals, Gene silencing, Gene Silencing, Epigenetics, 030304 developmental biology, Histone binding, MESH: DNA-Binding Proteins / genetics, epigenetics, TRIM28, MESH: Cytokines / metabolism, T-cell receptor, Gene Expression Regulation, Chromobox Protein Homolog 5, MESH: Autoimmunity / physiology, MESH: Colon / pathology, Transcriptome |
| الوصف: | Significance CD4 T cells are major regulators of immune responses against both self and pathogens. Understanding pathways that govern CD4 T cell differentiation and regulation are thus key for the discovery of new immunoregulatory drug targets. Here, we have identified an epigenetic pathway that regulates the expression of a set of proteins that determine T cell responsiveness. By silencing enhancers distal to a set of genes known to be involved in regulatory T cell function, the epigenetic modifiers TRIM28 and HP1β/γ regulate T cell receptor signaling. This leads to defective metabolic reprograming and inefficient effector differentiation of naive T cells. This mechanism provides an exciting opportunity to regulate T cell responsivity in both autoimmunity and T cell-based immunodeficiencies. 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. |
| اللغة: | English |
| تدمد: | 0027-8424 1091-6490 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dbdc87a7d673a9a3997e6fdd23ac6a75Test https://hal.archives-ouvertes.fr/hal-02369616/documentTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....dbdc87a7d673a9a3997e6fdd23ac6a75 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00278424 10916490 |
|---|