Genome-wide DNA methylation analysis identifies hypomethylated genes regulated by FOXP3 in human regulatory T cells

Abstract

Key Points• Human naive CD41 T cells and resting nTreg are differentially methylated at 127 regions in their genomic DNA.• Forkhead-binding motifs are present in promoterassociated differentially methylated regions, inferring broader epigenetic control of Treg.Regulatory T cells (Treg) prevent the emergence of autoimmune disease. Prototypic natural Treg (nTreg) can be reliably identified by demethylation at the Forkhead-box P3 (FOXP3) locus. To explore the methylation landscape of nTreg, we analyzed genomewide methylation in human naive nTreg (rTreg) and conventional naive CD4 1 T cells (Naive). We detected 2315 differentially methylated cytosine-guanosine dinucleotides (CpGs) between these 2 cell types, many of which clustered into 127 regions of differential methylation (RDMs). Activation changed the methylation status of 466 CpGs and 18 RDMs in Naive but did not alter DNA methylation in rTreg. Gene-set testing of the 127 RDMs showed that promoter methylation and gene expression were reciprocally related. RDMs were enriched for putative FOXP3-binding motifs. Moreover, CpGs within known FOXP3-binding regions in the genome were hypomethylated. In support of the view that methylation limits access of FOXP3 to its DNA targets, we showed that increased expression of the immune suppressive receptor T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT), which delineated Treg from activated effector T cells, was associated with hypomethylation and FOXP3 binding at the TIGIT locus. Differential methylation analysis provides insight into previously undefined human Treg signature genes and their mode of regulation. (Blood. 2013;122(16):2823-2836

Unravelling the molecular basis for regulatory T‐cell plasticity and loss of function in disease

“…The modifiable mediators of this regulation include methylation,37, 38, 39, 40, 41, 42, 43, 44 acetylation45, 46, 47 and microRNA‐mediated control of transcript translation 28, 48, 49, 50, 51, 52, 53, 54, 55. The global regulation of FOXP3 is influenced by chromatin organises, including SATB1 acts both during development and in mature cells 48, 58.…”

TIGIT and PD-1 impair tumor antigen–specific CD8+ T cells in melanoma patients

“…However, it was later demonstrated that TIGIT also exerts CD4 + T cell-intrinsic inhibitory effects via recruitment of SHP phosphatases that suppress cytokine production and proliferation (35,36) and competes with CD226 for PVR binding (37). The TIGIT locus is demethylated in Tregs and may potentially bind to FOXP3 (38). TIGIT + Tregs are highly activated, secrete the soluble effector molecule fibrinogen-like protein 2, and selectively inhibit Th1 and Th17 responses (39).…”

The DNA methylation profile of activated human natural killer cells

“…30 Table 2 illustrates more examples of differentially methylated genes from other activated immune cells that appear to be common with NK cell activation. [30][31][32][33][34][35][36][37][38][39] The Th2 cytokine locus has been intensively studied as a model of chromatin dynamics directing gene expression in the immune system. The genes encoding the Th2 cytokines IL4, IL5 and IL13 are clustered in a 160 kb region of chromosome 5q31 in humans.…”