Inflammation-induced repression of chromatin bound by the transcription factor Foxp3 in regulatory T cells

Abstract

The transcription factor Foxp3 is indispensable for the ability of regulatory T (Treg) cells to suppress fatal inflammation. Here, we characterized the role of Foxp3 in chromatin remodeling and regulation of gene expression in actively suppressing Treg cells in an inflammatory setting. Although genome-wide Foxp3 occupancy of DNA regulatory elements was similar in resting and in vivo activated Treg cells, Foxp3-bound enhancers were poised for repression only in activated Treg cells. Following activation, Foxp3-bound sites showed reduced chromatin accessibility and selective H3K27 tri-methylation, which was associated with Ezh2 recruitment and downregulation of nearby gene expression. Thus, Foxp3 poises its targets for repression by facilitating formation of repressive chromatin in regulatory T cells upon their activation in response to inflammatory cues.

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…H3K27 HMT EZH2, acting within PRC2, interacts directly with FOXP3 and is required for the main tenance of the transcriptional programme and function of activated T Reg cells 151,152 . During in vitro polarization, the activity of EZH2 also prevents plasticity between T H 1 and T H 2 cell subsets and supports pT Reg cell generation by inhibiting IFNγ expression 153,154 .…”

MRTF-A mediates LPS-induced pro-inflammatory transcription by interacting with the COMPASS complex

“…Second, the current study focuses entirely on the proximal promoter region, whereas the role of distal regulatory elements is left unaddressed. Numerous investigations have established that epigenetic events taking place at enhancers are key to inflammation-related transcription (Arvey et al, 2014;Ghisletti et al, 2010;Li et al, 2013). It is possible that different isoforms of MRTF-A might interact with different sites to drive pro-inflammatory transcription.…”

Epigenetics of gastrointestinal diseases: notes from a workshop

“…These cells are defined by the expression of the lineage-specific expression of the transcription factor Forkhead Box P3 (FOXP3) [15]. Dr. Faubion’s group and others have shown that FOXP3 recruits EZH2 to repress gene expression [16,17]. Transgenic mouse studies in which the EZH2 SET domain (which carries the methyltransferase activity of EZH2) was deleted in FOXP3+ cells demonstrated that Ezh2 ΔSET/ΔSET -Tregs did not show a regulator phenotype and secreted proinflammatory cytokines, unlike Tregs from Ezh2 +/+ mice.…”