1. NFAT primes the human RORC locus for RORγt expression in CD4+ T cells
- Author
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Elisabetta Bianchi, Lars Rogge, Tharshana Stephen, Magda Rybczynska, Domenica Lovecchio, Hanane Yahia-Cherbal, Chloé Lescale, Jérôme Larghero, Katarzyna Placek, Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Immunorégulation - Immunoregulation, Institut Pasteur [Paris], Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Département de Génomes et Génétique - Department of Genomes and Genetics, Département d'Immunologie - Department of Immunology, Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer, CIC - Biotherapie - Saint Louis ((CIC-BT 301)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Grants from Institut Pasteur, FOREUM Foundation for Research in Rheumatology, the Fondation Arthritis, MSD Avenir (Project iCARE-SpA), and a Bourse Passerelle from Pfizer., Center for Translational Research/Cytometry Biomarkers Unit of Technology and Service (CRT/CB UTechS), Institut Pasteur. Estelle Mottez (CRT/CB UTechS) : drafting of clinical protocols. O. Kaminuma, F. Berberich-Siebelt and G. Natoli: expression constructs (see Methods). Helène Strick-Marchand (Innate Immunity Unit, Institut Pasteur) for human hepatocytes lysates., Institut Pasteur [Paris] (IP), and Kop, Marie-Luce
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0301 basic medicine ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,Science ,[SDV]Life Sciences [q-bio] ,Adaptive immunity ,General Physics and Astronomy ,Biology ,Jurkat cells ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,RAR-related orphan receptor gamma ,Histone code ,NF-kappaB ,T-helper 17 cells ,lcsh:Science ,Transcription factor ,Regulation of gene expression ,Multidisciplinary ,NFAT ,General Chemistry ,NFATC Transcription Factors ,Cell biology ,[SDV] Life Sciences [q-bio] ,Thymocyte ,Gene regulation in immune cells ,030104 developmental biology ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,lcsh:Q ,030215 immunology - Abstract
T helper 17 (Th17) cells have crucial functions in mucosal immunity and the pathogenesis of several chronic inflammatory diseases. The lineage-specific transcription factor, RORγt, encoded by the RORC gene modulates Th17 polarization and function, as well as thymocyte development. Here we define several regulatory elements at the human RORC locus in thymocytes and peripheral CD4+ T lymphocytes, with CRISPR/Cas9-guided deletion of these genomic segments supporting their role in RORγt expression. Mechanistically, T cell receptor stimulation induces cyclosporine A-sensitive histone modifications and P300/CBP acetylase recruitment at these elements in activated CD4+ T cells. Meanwhile, NFAT proteins bind to these regulatory elements and activate RORγt transcription in cooperation with NF-kB. Our data thus demonstrate that NFAT specifically regulate RORγt expression by binding to the RORC locus and promoting its permissive conformation., The master transcription factor RORγt, encoded by the RORC gene, controls the polarization of CD4+ T cells expressing interleukin-17 (Th17). Here the authors describe several regulatory elements at the RORC locus that are recognized by NFAT and NFkB to induce a permissive epigenetic configuration of the RORC gene for RORγt expression and Th17 differentiation.
- Published
- 2019
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