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

Nat Commun. 2019 Oct 16;10(1):4698. doi: 10.1038/s41467-019-12680-x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / metabolism
  • CRISPR-Cas Systems
  • Cell Lineage
  • Flow Cytometry
  • Gene Expression Regulation*
  • HEK293 Cells
  • Histone Code
  • Humans
  • Jurkat Cells
  • NFATC Transcription Factors / metabolism*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics*
  • Regulatory Elements, Transcriptional / genetics*
  • Th17 Cells / cytology
  • Th17 Cells / metabolism*
  • Thymocytes / cytology
  • Thymocytes / metabolism*
  • Transcriptional Activation*
  • p300-CBP Transcription Factors / metabolism


  • NFATC Transcription Factors
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • RORC protein, human
  • p300-CBP Transcription Factors