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.
Highlights
T cells into functionally distinct T helper (Th) subsets, characterized by the secretion of specific “cytokine signatures”
Differentiation of Th subsets requires the integration of signals generated by the engagement of the T cell receptor (TCR) and by cytokines present at the time of stimulation: Th1 cells are generated in the presence of IL-12 or IFNγ, while IL-4 promotes Th2 differentiation[1]
In this work we explore epigenetic and transcriptional mechanisms associated with human RORγt expression in thymocytes and in vitro differentiating T helper 17 (Th17) cells, with particular attention for TCR-activated signaling pathways
Summary
T cells into functionally distinct T helper (Th) subsets, characterized by the secretion of specific “cytokine signatures”. Differentiation is maintained by a network of subset-specific transcription factors and is stabilized through multiple cell divisions by epigenetic processes that regulate accessibility of regulatory chromatin regions, and promote heritable gene expression patterns. These epigenetic circuits can maintain cell identity when the initial signals driving differentiation are extinct[6]. In Th17 cells, the Il17a and Il17f loci are enriched for histone marks associated with a permissive chromatin conformation, such as Histone 3 acetylation (H3Ac) and Histone 3 Lysine 4 trimethylation (H3K4me3)[9] These histone modifications contribute to creating an open chromatin environment for the binding of transcription factors to these loci.
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