NFAT primes the human RORC locus for RORγt expression in CD4 + T cells

Hanane Yahia-Cherbal (1, 2) , Magda Rybczynska (2) , Domenica Lovecchio (2) , Tharshana Stephen (3) , Chloé Lescale (4, 5, 6) , Katarzyna Placek (2) , Jerome Larghero (7) , Lars Rogge (2) , Elisabetta Bianchi (2)

1 Cellule Pasteur
2 Immunorégulation - Immunoregulation
3 UTechS CB - Cytometrie et Biomarqueurs – Cytometry and Biomarkers
4 Département de Génomes et Génétique - Department of Genomes and Genetics
5 Département d'Immunologie - Department of Immunology
6 Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer
7 (CIC-BT 301) - CIC - Biotherapie - Saint Louis

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 thy-mocytes 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.

Domains: Life Sciences [q-bio]; Immunology

Hanane Yahia-Cherbal, Magda Rybczynska, Domenica Lovecchio, Tharshana Stephen, Chloé Lescale, et al.. NFAT primes the human RORC locus for RORγt expression in CD4 + T cells. Nature Communications, 2019, 10 (1), pp.4698. ⟨10.1038/s41467-019-12680-x⟩. ⟨pasteur-02626213⟩