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The Conserved Non-Coding Sequence CNS11 Is A Master Control Region for Rorc Transcription in Type 17 Immune Cells [4C-Seq]

ABSTRACT: As the master transcription factor, RORγt controls the development and function of all type 17 immune cells. Although the trans-regulatory mechanisms governing Rorc expression have been extensively studied, the cis-regulatory mechanisms that differentially regulate Rorc transcription across distinct lymphocytes, particularly in innate lymphocytes, remain largely unknown. Here, we identified CNS11 at the Rorc gene as essential for the development of all type 17 immune cells. Deletion of CNS11 impaired the maintenance but not induction of Th17 cells, abolished the development of RORγt+ Treg cells, RORγt+ γδT cells and RORγt+ antigen-presenting cells, and blocked ILC3 induction from early progenitors, leading to a complete absence of secondary lymphoid organs. Mechanistically, CNS11 mediates the Rorc transcription through a RORγt-dependent feedforward regulatory loop in a cell-type-specific manner. Specifically, the interaction of CNS11 with RORγt and RUNX3 dictated the development of ILC3s, while its interaction with RORγt and/or c-MAF was crucial for RORγt expression in Th17 cells, RORγt+ Treg cells and RORγt+ γδT cells. Our study reveals CNS11 as a key transcription factor binding hub and master control region for Rorc transcription in distinct lymphocytes.

ORGANISM(S): Mus musculus

PROVIDER: GSE297569 | GEO | 2026/02/17

REPOSITORIES: GEO

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The Conserved Non-Coding Sequence CNS11 Is A Master Control Region for Rorc Transcription in Type 17 Immune Cells [CUT&Tag]

Project description:As the master transcription factor, RORγt controls the development and function of all type 17 immune cells. Although the trans-regulatory mechanisms governing Rorc expression have been extensively studied, the cis-regulatory mechanisms that differentially regulate Rorc transcription across distinct lymphocytes, particularly in innate lymphocytes, remain largely unknown. Here, we identified CNS11 at the Rorc gene as essential for the development of all type 17 immune cells. Deletion of CNS11 impaired the maintenance but not induction of Th17 cells, abolished the development of RORγt+ Treg cells, RORγt+ γδT cells and RORγt+ antigen-presenting cells, and blocked ILC3 induction from early progenitors, leading to a complete absence of secondary lymphoid organs. Mechanistically, CNS11 mediates the Rorc transcription through a RORγt-dependent feedforward regulatory loop in a cell-type-specific manner. Specifically, the interaction of CNS11 with RORγt and RUNX3 dictated the development of ILC3s, while its interaction with RORγt and/or c-MAF was crucial for RORγt expression in Th17 cells, RORγt+ Treg cells and RORγt+ γδT cells. Our study reveals CNS11 as a key transcription factor binding hub and master control region for Rorc transcription in distinct lymphocytes.

2026-02-17 | GSE297567 | GEO

RORγt expression in mature Th17 cells safeguard the lineage stability by inhibiting conversion to Th2 cells [RNA-Seq]

Project description:RORγt is the lineage-specific transcription factor for T helper 17 (Th17) cells and an attractive drug target for treating Th17-associated diseases. Though the critical role of RORγt in early Th17 cell differentiation has been well recognized, whether it maintains mature Th17 cell phenotypes remains largely unexplored. Here, we show that genetic deletion of Rorc in mature Th17 cells inhibited their pathogenic functions. Mechanistically, loss of RORγt led to a closed chromatin structure at key Th17-specific gene loci, particularly at those so called “super enhancer” regions. Furthermore, RORc deletion in effector Th17 cells resulted in a strongly Th2-biased cell phenotype at both epigenetic and transcriptional levels, in an IL-4-dependent manner. Our results thus reveal a crucial function of RORγt in effector Th17 cells in maintaining Th17 cell program and constraining Th2 cell conversion, offering new considerations in therapeutic targeting of RORγt.

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RORγt expression in mature Th17 cells safeguard the lineage stability by inhibiting conversion to Th2 cells [ATAC-seq]

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RORγt⁺ Dendritic Cells Are a Distinct Lymphoid-Derived Lineage [CITE-seq]

Project description:How tolerogenic dendritic cell (DC) lineages are established to prevent inappropriate immune responses to commensals and food antigens remains unclear. We identify RORγt⁺ DCs in mice as a distinct lymphoid-derived lineage to safeguard intestinal tolerance. Using lineage tracing and single-cell transcriptomics, we unveiled bone marrow–resident Rorc(t)⁺ progenitors, which include a RORγt⁺ innate lymphoid progenitor (RILP) that generates both ILC3s and RORγt⁺ DCs, and a pre-RORγt⁺ DC precursor committed exclusively to the RORγt⁺ DC lineage. RORγt⁺ DC development required the Rorc +7 kb enhancer, whose accessibility was ensured by the repressors REV-ERBα and REV-ERBβ, and depended on the transcription factors PRDM16 and PU.1 for lineage commitment. Loss of any of these regulators abrogated RORγt⁺ DC differentiation, reduced peripheral regulatory T (Treg) cell induction, and skewed toward T helper 2 responses. Together, these findings define murine RORγt⁺ DCs as a lymphoid-derived lineage whose enhancer- and transcription factor–driven development is essential for peripheral Treg cell-mediated immune homeostasis.

2026-01-26 | GSE312479 | GEO

RORγt⁺ Dendritic Cells Are a Distinct Lymphoid-Derived Lineage

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Generation of RORγt+ antigen-specific T regulatory 17 (Tr17) cells from Foxp3+ precursors in autoimmunity

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.

2017-08-31 | GSE103319 | GEO

Chemical Inhibition of the RORγt-dependent Transcriptional Network in Th17 cells [ChIP-Seq]

Project description:RORγt is a transcription factor required for T helper 17 (Th17) cell development. We identified three RORγt-specific inhibitors that suppress Th17 cell responses including Th17 cell-mediated autoimmune disease. We systemically characterized RORγt binding data in the presence and absence of drug with corresponding whole-transcriptome sequencing for wild-type and RORγt-deficient cells. RORγt is central in a densely interconnected regulatory network, acting both as a direct activator of genes important for Th17 cell differentiation and as a direct repressor of genes from other T-cell lineages. The three inhibitors identified here reversed both of these modes of action, but to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target-loci, the two more potent inhibitors affected transcription predominantly without removing DNA-binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity. DNA binding of RORγt in WT Th17 cells and under chemical perturbations of RORγt; Additional data is included for epitope-tagged exogenous RORγt in EL4 cells (a murine lymphoma cell line)

2014-04-17 | E-GEOD-56019 | biostudies-arrayexpress

Chemical Inhibition of the RORγt-dependent Transcriptional Network in Th17 cells [RNA-Seq 2]

Project description:RORγt is a transcription factor required for T helper 17 (Th17) cell development. We identified three RORγt-specific inhibitors that suppress Th17 cell responses including Th17 cell-mediated autoimmune disease. We systemically characterized RORγt binding data in the presence and absence of drug with corresponding whole-transcriptome sequencing for wild-type and RORγt-deficient cells. RORγt is central in a densely interconnected regulatory network, acting both as a direct activator of genes important for Th17 cell differentiation and as a direct repressor of genes from other T-cell lineages. The three inhibitors identified here reversed both of these modes of action, but to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target-loci, the two more potent inhibitors affected transcription predominantly without removing DNA-binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity. Transcriptional profiling of Th17 cells under chemical perturbations of RORγt, DMSO, and knockout of RORγt. It includes repeats for all the data in GSE56018, plus one additional condition.

2014-04-17 | E-GEOD-56240 | biostudies-arrayexpress

RORγt+ APCs require a distinct cis-regulatory element to instruct tolerance to dietary antigens [RNA-seq]

Project description:RORγt is the linage-specific transcription factor for both ILC3 and T-helper 17 (Th17) counterparts, who take an essential place in regulating intestinal homeostasis. While the biological significance of high RORγt expression and its distinct regulatory mechanisms in ILC3s remains investigation. Through comparing ATAC-seq results on ILC3 and Th17 cells, we identified an open chromatin region (OCR369) which specifically regulates ILC3 RORγt expression and development. Mechanistically, OCR369 is bind by the RORγt activator RUNX3, and is also involved in the chromatin-loop formation between OCR369 and RORγt-promoter. OCR369 depletion also impaired the MHCII+ ILC3s, a group of antigen-presenting cells that regulate RORγt+ Treg cells. And disruption of Th/ Treg balance in the OCR369-deficient mice leads to the spontaneous type 2 inflammation in the small intestine, and impaired generation of oral tolerance. Thus, our study revealed a specific RORγt amplifying mechanism in ILC3 and its important role in maintaining intestinal immune environment and food tolerance.

2026-01-31 | GSE274080 | GEO

A hierarchical Rorc(γt) cis-regulatory cascade orchestrates differentiation of RORγt⁺ innate immune cells [ChIP-seq]

Project description:Beyond its well-established role in type 3 immunity, RORγt+ innate immune cells are also essential for secondary lymphoid organ (SLO) formation and gut homeostasis. However, the transcriptional regulatory mechanisms governing RORγt expression in these cells, including ILC3s, LTi cells, and antigen-presenting cells (APCs), remain largely unknown. Here, we identify two key cis-regulatory elements within conserved non-coding sequences (CNS) 9 and 11 in the Rorc locus, which are sequentially utilized during their differentiation. Initially, Runx-binding sites in CNS11 establish chromatin accessibility as early as the HSC stage. Notably, disruption of this chromatin priming prevents subsequent transcriptional activation, thereby abolishing the initial induction of RORγt in these cells. At later stages, CNS9 plays a critical role, particularly in the development of RORγt⁺ APCs, contributing to colonic pTreg induction. This hierarchical transcriptional regulation is essential for SLO formation, postnatal type 3 immunity, and restraining excessive intestinal type 2 immune responses through pTreg induction.

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