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Genome-wide binding of STAT3 and STAT5 under Th17 conditions (ChIP-Seq)

ABSTRACT: Interleukin 2 (IL-2), a cytokine linked to human autoimmune diseases, limits IL-17 production. We show that deletion of Stat3 in T cells abrogates IL-17 production and attenuates autoimmunity associated with IL-2 deficiency. While STAT3 induces IL-17 and RORγt and inhibits Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and RORγt. We found that STAT3 and STAT5 bound to multiple common sites across the Il17 genetic locus. The induction of STAT5 binding by IL-2 was associated with a reduction in STAT3 binding at these sites and the inhibition of associated active epigenetic marks. Titrating the relative activation of STAT3 and STAT5 modulated TH17 cell specification. Thus, the balance rather than the absolute magnitude of these signals determines the propensity of cells to make a key inflammatory cytokine.

ORGANISM(S): Mus musculus

PROVIDER: GSE26552 | GEO | 2011/02/09

SECONDARY ACCESSION(S): PRJNA142287

REPOSITORIES: GEO

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Genome-wide binding of STAT3 and STAT5 under Th17 conditions (ChIP-Seq)

Project description:Interleukin 2 (IL-2), a cytokine linked to human autoimmune diseases, limits IL-17 production. We show that deletion of Stat3 in T cells abrogates IL-17 production and attenuates autoimmunity associated with IL-2 deficiency. While STAT3 induces IL-17 and RORγt and inhibits Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and RORγt. We found that STAT3 and STAT5 bound to multiple common sites across the Il17 genetic locus. The induction of STAT5 binding by IL-2 was associated with a reduction in STAT3 binding at these sites and the inhibition of associated active epigenetic marks. Titrating the relative activation of STAT3 and STAT5 modulated TH17 cell specification. Thus, the balance rather than the absolute magnitude of these signals determines the propensity of cells to make a key inflammatory cytokine. The genome-wide binding of STAT3 and STAT5 under Th17 conditions was investigated by CHIP-seq.

2011-02-09 | E-GEOD-26552 | biostudies-arrayexpress

Roles of STAT3 and STAT5 in regulation of gene expression under Th17 differentiation

2011-02-09 | GSE26551 | GEO

Roles of STAT3 and STAT5 in regulation of gene expression under Th17 differentiation

Project description:Interleukin 2 (IL-2), a cytokine linked to human autoimmune diseases, limits IL-17 production. We show that deletion of Stat3 in T cells abrogates IL-17 production and attenuates autoimmunity associated with IL-2 deficiency. While STAT3 induces IL-17 and ROR?t and inhibits Foxp3, IL-2 inhibited IL-17 independently of Foxp3 and ROR?t. We found that STAT3 and STAT5 bound to multiple common sites across the Il17 genetic locus. The induction of STAT5 binding by IL-2 was associated with a reduction in STAT3 binding at these sites and the inhibition of associated active epigenetic marks. Titrating the relative activation of STAT3 and STAT5 modulated TH17 cell specification. Thus, the balance rather than the absolute magnitude of these signals determines the propensity of cells to make a key inflammatory cytokine. The roles of STAT3 and STAT5 in regulation of gene expression under Th17 differentiation was investigated. Affymetrix Mouse Genome 430 2.0 Arrays were used to evaluate global gene expression.

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Project description:Cell fate decision is mediated by epigenetic mechanisms. We have analyzed naive T cell differentiation into Th17 cells, which is regulated by environmental cytokines and their downstream transcription factors. RORγt is a lineage-specific master transcription factor for Th17 cells. Although epigenetic mechanisms have been implicated in Th17 cell differentiation, how transcription factors interact to activate epigenetic program is unclear. Here we show that tripartite motif containing 28 (TRIM28) expression in Th17 cells is required for cytokine production and autoimmune diseases. Genome-wide occupancy analysis reveals that TRIM28 bound regions contain many super-enhancers, which are impaired after TRIM28 or STAT3 but not RORγt deletion. Importantly, TRIM28 exists in a complex with STAT3 and RORγt; TRIM28 recruitment to the Il17 gene requires STAT3, and further promotes RORγt recruitment. TRIM28 thus is a key player in the epigenetic activation during T cell differentiation.

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Project description:Th17 cells are potent mediators in autoimmune diseases and RORγt is required for their development. Recent studies have shown that RORγt+ Treg cells in the gut regulate intestinal inflammation by inhibiting effector T cell function. In the current study, we report that RORγt+ Treg cells were also found in lymph nodes following immunization. Not only distinct from intestinal RORγt+ Treg in their transcriptomes, peripheral RORγt+ Treg cells were derived from Foxp3+ thymic Treg cells, in an antigen-specific manner. Development of these RORγt+ Treg cells, coined as T regulatory 17 (Tr17) cells, depended on IL-6/Stat3 signaling. Tr17 cells showed suppressive activity against antigen-specific effector T cells in vitro. In addition, Tr17 cells efficiently inhibited myelin-specific Th17 cell-mediated CNS auto-inflammation in a passive EAE model. Collectively, our study demonstrates Tr17 cells as effector Treg cells that potentially restrict autoimmunity.

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