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Foxp3 exploits a preexistent enhancer landscape for regulatory T cell lineage specification [Expression]

ABSTRACT: Regulatory T (Treg) cells, whose identity and function are defined by the transcription factor Foxp3, are indispensable for immune homeostasis. It is unclear whether Foxp3 exerts its Treg lineage specification function through active modification of the chromatin landscape and establishment of new enhancers or by exploiting a pre-existing enhancer landscape. Analysis of the chromatin accessibility of Foxp3-bound enhancers in Treg and Foxp3-negative T cells showed that Foxp3 was bound overwhelmingly to pre-accessible enhancers occupied by its cofactors in precursor cells or a structurally related predecessor. Furthermore, the bulk of Foxp3-bound Treg cell enhancers inaccessible in Foxp3- CD4+ cells became accessible upon T cell receptor activation prior to Foxp3 expression with only a small subset associated with several functionally important genes being exclusively Treg cell-specific. Thus, in a late cellular differentiation process Foxp3 defines Treg cell functionality in an “opportunistic” manner by largely exploiting the preformed enhancer network instead of establishing a new enhancer landscape.

ORGANISM(S): Mus musculus

PROVIDER: GSE40685 | GEO | 2012/09/28

SECONDARY ACCESSION(S): PRJNA174614

REPOSITORIES: GEO

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Foxp3 exploits a preexistent enhancer landscape for regulatory T cell lineage specification [Expression]

Project description:Regulatory T (Treg) cells, whose identity and function are defined by the transcription factor Foxp3, are indispensable for immune homeostasis. It is unclear whether Foxp3 exerts its Treg lineage specification function through active modification of the chromatin landscape and establishment of new enhancers or by exploiting a pre-existing enhancer landscape. Analysis of the chromatin accessibility of Foxp3-bound enhancers in Treg and Foxp3-negative T cells showed that Foxp3 was bound overwhelmingly to pre-accessible enhancers occupied by its cofactors in precursor cells or a structurally related predecessor. Furthermore, the bulk of Foxp3-bound Treg cell enhancers inaccessible in Foxp3- CD4+ cells became accessible upon T cell receptor activation prior to Foxp3 expression with only a small subset associated with several functionally important genes being exclusively Treg cell-specific. Thus, in a late cellular differentiation process Foxp3 defines Treg cell functionality in an “opportunistic” manner by largely exploiting the preformed enhancer network instead of establishing a new enhancer landscape. Array expression. Three cell types with 3-5 replicates each.

2012-09-28 | E-GEOD-40685 | biostudies-arrayexpress

Foxp3 exploits a preexistent enhancer landscape for regulatory T cell lineage specification [ChIP-Seq]

Project description:Regulatory T (Treg) cells, whose identity and function are defined by the transcription factor Foxp3, are indispensable for immune homeostasis. It is unclear whether Foxp3 exerts its Treg lineage specification function through active modification of the chromatin landscape and establishment of new enhancers or by exploiting a pre-existing enhancer landscape. Analysis of the chromatin accessibility of Foxp3-bound enhancers in Treg and Foxp3-negative T cells showed that Foxp3 was bound overwhelmingly to pre-accessible enhancers occupied by its cofactors in precursor cells or a structurally related predecessor. Furthermore, the bulk of Foxp3-bound Treg cell enhancers lacking in Foxp3- CD4+ cells became accessible upon T cell receptor activation prior to Foxp3 expression with only a small subset associated with several functionally important genes being exclusively Treg cell-specific. Thus, in a late cellular differentiation process Foxp3 defines Treg cell functionality in an “opportunistic” manner by largely exploiting the preformed enhancer network instead of establishing a new enhancer landscape. Four transcription factors (Foxp3, Ets1, Elf1, and Cbfb) were immunoprecipated while crosslinked to chromatin. These experiments were then combined with DNase-seq data (being uploaded separately as part of ENCODE project) to find that Foxp3 binds exclusively to open chromatin. Data was also leveraged from GSE40657 and GSE33653.

2012-09-28 | E-GEOD-40684 | biostudies-arrayexpress

Foxp3 exploits a preexistent enhancer landscape for regulatory T cell lineage specification [ChIP-Seq]

Project description:Regulatory T (Treg) cells, whose identity and function are defined by the transcription factor Foxp3, are indispensable for immune homeostasis. It is unclear whether Foxp3 exerts its Treg lineage specification function through active modification of the chromatin landscape and establishment of new enhancers or by exploiting a pre-existing enhancer landscape. Analysis of the chromatin accessibility of Foxp3-bound enhancers in Treg and Foxp3-negative T cells showed that Foxp3 was bound overwhelmingly to pre-accessible enhancers occupied by its cofactors in precursor cells or a structurally related predecessor. Furthermore, the bulk of Foxp3-bound Treg cell enhancers lacking in Foxp3- CD4+ cells became accessible upon T cell receptor activation prior to Foxp3 expression with only a small subset associated with several functionally important genes being exclusively Treg cell-specific. Thus, in a late cellular differentiation process Foxp3 defines Treg cell functionality in an “opportunistic” manner by largely exploiting the preformed enhancer network instead of establishing a new enhancer landscape.

2012-09-28 | GSE40684 | GEO

Foxp3 exploits a preexistent enhancer landscape for regulatory T cell lineage specification

Project description:This SuperSeries is composed of the following subset Series: GSE40684: Foxp3 exploits a preexistent enhancer landscape for regulatory T cell lineage specification [ChIP-Seq] GSE40685: Foxp3 exploits a preexistent enhancer landscape for regulatory T cell lineage specification [Expression] Refer to individual Series

2012-09-28 | E-GEOD-40686 | biostudies-arrayexpress

Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape

Project description:<p>Transcription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. Mutations in the p63 DNA-binding domain are associated with Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate (EEC) syndrome. Underlying molecular mechanism of these mutations however remain unclear. Here we characterized the transcriptome and epigenome of p63 mutant keratinocytes derived from EEC patients. The transcriptome of p63 mutant keratinocytes deviated from the normal epidermal cell identity. Epigenomic analyses showed an altered enhancer landscape in p63 mutant keratinocytes contributed by loss of p63-bound active enhancers and by unexpected gain of enhancers. The gained enhancers were frequently bound by deregulated transcription factors such as RUNX1. Reversing RUNX1 overexpression partially rescued deregulated gene expression and the altered enhancer landscape. Our findings identify an unreported disease mechanism whereby mutant p63 rewires the enhancer landscape and affects epidermal cell identity, consolidating the pivotal role of p63 in controlling the enhancer landscape of epidermal keratinocytes.</p>

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Inflammation induced repression of Foxp3-bound chromatin in regulatory T cells [microarray]

Project description: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. The supplementary file GSE55705_dt_expr.txt is a matrix for Treg expression data from platform GPL1261 that includes co-normalized data from GSE40685. array expression

2014-04-12 | E-GEOD-55705 | biostudies-arrayexpress

MLL4 prepares the enhancer landscape for FoxP3 induction via chromatin looping

Project description:MLL4 is an essential subunit of the H3K4 methylation complexes. We report that Mll4 deficiency compromised Treg development and resulted in substantial decreases in H3K4me1 and chromatin interaction at putative enhancers, a remarkable portion of which were not direct targets of MLL4 but were interacting with Mll4-bound sites. The decrease in H3K4me1 and chromatin interaction at the MLL4-unbound enhancers correlated with MLL4 binding at distant interacting regions. Deletion of an upstream MLL4 binding site reduced H3K4me1 at the FoxP3 regulatory elements looped to the MLL4 binding site and compromised both tTreg and iTreg differentiation. We show that MLL4 catalyses H3K4 methylation at distant unbound enhancers via chromatin looping, thus providing a new mechanism of regulating T cell enhancer landscape and impacting Treg differentiation.

2017-07-18 | GSE69162 | GEO

Inflammation induced repression of Foxp3-bound chromatin in regulatory T cells [sequencing]

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2014-04-12 | E-GEOD-55773 | biostudies-arrayexpress

Inflammation induced repression of Foxp3-bound chromatin in regulatory T cells [sequencing]

Project description: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. The supplementary file foxp3_rest_act_table.txt includes Foxp3 ChIP data that is co-normalized with data from Foxp3 ChIP data from GSE40684.

2014-04-12 | GSE55773 | GEO

Inflammation induced repression of Foxp3-bound chromatin in regulatory T cells [microarray]

2014-04-12 | GSE55705 | GEO