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Comprehensive mapping of epigenetic events during the T-follicular helper-to-T-regulatory type-1 transdifferentiation pathway reveal a global poised state

ABSTRACT: Chronic antigenic stimulation can trigger the formation of IL-10-producing T-regulatory type 1 (TR1) cells in vivo. We have recently shown that T follicular helper cells are precursors of TR1 cells and that the TFH-to-TR1 cell transdifferentiation process is underpinned by the progressive loss and acquision of opposing transcription factor gene expression programs that evolve through at least one transitional cell stage. Through a combination of wide-ranging bulk and single-cell transcriptional and epigenetic studies, here we demonstrate that TFH cells are epigenetically poised to differentiate into TR1 cells. Specifically, we find that the TFH-to-TR1 cell transition is accompanied by a significant reduction of the open chromatin regions (OCRs) found in TFH cells. However, the OCRs shared by TR1-like and TFH cells have a remarkably similar distribution of H3K27ac-marked active enhancers. Whereas the DNA regions that overlap these active enhancers are closed and hyper-methylated in conventional T cells, they are hypo-methylated in both TFH and TR1-like cells, even in genes silent in TFH cells, such as Il10. Furthermore, these enhancers are enriched for binding sites for the TFH and TR1-associated transcription factors (TFs) TOX-2, IRF4 and c-Maf. These data suggest that TFH cells are epigenetically poised to become TR1 cells, and that sustained TCR ligation-induced chromatin remodeling coupled to the acquisition of an alternative transcription factor expression profile are sufficient to drive their transdifferentiation into TR1 cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE248152 | GEO | 2024/11/07

REPOSITORIES: GEO

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Project description:Cell fate transitions involve integration of genomic information encoded by regulatory elements, such as enhancers, with the cellular environment. However, identification of the genomic sequences that control the earliest steps of human embryonic development represents a formidable challenge. Here we show that in human embryonic stem cells (hESCs) unique chromatin signatures identify two distinct classes of genomic elements, both of which are marked by the presence of chromatin regulators p300 and BRG1, and monomethylation of histone H3 at lysine 4 (H3K4me1). In addition, the elements of the first class are distinguished by the acetylation of histone H3 at lysine 27 (H3K27ac), overlap with previously characterized enhancers active in hESCs, and are generally located proximally to genes expressed in hESCs and in the epiblast. In contrast, the elements within the second class, which we termed M-bM-^@M-^\poised enhancersM-bM-^@M-^], are distinguished by the absence of H3K27ac, enrichment of histone H3 lysine 27 trimethylation (H3K27me3) and are linked to genes inactive in hESCs and involved in orchestrating early steps in mammalian development, such as gastrulation, mesoderm formation and neurulation. Consistent with the poised identity, during differentiation of hESCs to neuroepithelium, a neuroectoderm-specific subset of these elements acquires a chromatin signature associated with active enhancers. Remarkably, when assayed in zebrafish embryos, human poised enhancer elements are able to direct cell type and stage specific expression patterns characteristic of their proximal developmental gene, even in the absence of sequence conservation in the fish genome. Our data demonstrate that enhancers are epigenetically pre-marked and suggest a heretofore unappreciated role of H3K27me3 at distal regulatory elements. Moreover, the unique chromatin signature associated with poised enhancers allowed us to uncover over 2,000 putative developmental regulatory sequences, thereby creating an invaluable resource for future studies and isolation of transient, rare cell populations representing early steps of human development. For GSM602289-90: RNA-seq experiments in human ESC and neuroectodermal (NEC) speheres For GSM602291-303: Genome-wide analysis of p300, H3K4me3, H3K4me1, H3K27me3 and H3K27ac in human embryonic stem cells (ESC) and neuroectoderm cells (NEC). Additionally, in H9 ESC ChIP-seq were alsoe obtained for BRG1 and FAIRE-seq was also performed.

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Comprehensive mapping of epigenetic events during the T-follicular helper-to-T-regulatory type-1 transdifferentiation pathway reveal a global poised state

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