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RORa enforces stability of the T-helper-17 cell effector program (ChIP-Seq (2))

ABSTRACT: Chronic inflammation is responsible for a number of debilitating human diseases including inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. The Th17 subset of T lymphocytes is an important player in the development of these pathogenic conditions. The transcription factor, RORgt was initially coined the master regulator of the Th17 program, but targeting RORgt therapeutically is dangerous owing to an enhanced risk of thymoma upon its inhibition. Another ROR family member, RORa, has also been implicated in Th17 function.

ORGANISM(S): Mus musculus

PROVIDER: GSE163341 | GEO | 2022/10/25

REPOSITORIES: GEO

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RORa enforces stability of the T-helper-17 cell effector program (ATAC-Seq)

Project description:Chronic inflammation is responsible for a number of debilitating human diseases including inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. The Th17 subset of T lymphocytes is an important player in the development of these pathogenic conditions. The transcription factor, RORgt was initially coined the master regulator of the Th17 program, but targeting RORgt therapeutically is dangerous owing to an enhanced risk of thymoma upon its inhibition. Another ROR family member, RORa, has also been implicated in Th17 function.

2022-10-25 | GSE163340 | GEO

RORa enforces stability of the T-helper-17 cell effector program (ChIP-Seq)

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RORa enforces stability of the T-helper-17 cell effector program (RNA-Seq)

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Genetic and pharmacological inhibition of the nuclear receptor RORa regulates Th17 driven inflammatory disorders

Project description:Full development of IL-17 producing CD4+ T helper cells (TH17 cells) requires the transcriptional activity of both orphan nuclear receptors RORa and RORgt. Despite this evidence, RORa is considered functionally redundant to RORgt; thus, the function and therapeutic value of RORa in TH17 cells remains underexplored. Using mouse models of autoimmune and chronic inflammation, we show that expression of RORa is required for TH17 cell pathogenicity. T-cell specific deletion of RORa reduced the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation was associated with decreased TH17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3+ T regulatory (Treg) cells. Importantly, inhibition of RORa with a selective small molecule antagonist largely phenocopied our genetic data, potently suppressing the in vivo development of both chronic/progressive and relapsing/remitting EAE but had no effect on overall thymic cellularity. Furthermore, use of the RORa antagonist effectively inhibited human TH17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORa acts independently of RORgt in programming TH17 pathogenicity and identifies RORa as a safer and more selective therapeutic target for the treatment of TH17-mediated autoimmunity.

2020-10-29 | GSE160327 | GEO

The nuclear receptor REV-ERBa modulates Th17 cell differentiation and function by competing with RORgt

Project description:T helper 17 (Th17) cells produce interleukin-17 (IL-17) cytokines and drive inflammatory responses in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. The differentiation of Th17 cells is dependent on the retinoic acid receptor-related orphan nuclear receptor RORgt. Here we identify REV-ERBa (encoded by Nr1d1), a member of the nuclear hormone receptor family (NHR), as a transcriptional repressor that antagonizes RORgt function in Th17 cells. REV-ERBa binds to ROR response elements (RORE) in Th17 cells and inhibits the expression of RORgt-dependent genes such as Il17a and Il17f. Furthermore, elevated REV-ERBa expression or treatment with a synthetic REV-ERB agonist significantly delays the onset and impedes the progression of experimental autoimmune encephalomyelitis (EAE), a Th17 cell-mediated autoimmune disease. These results suggest that modulating REV-ERB activity may hold therapeutic potential for treatment of Th17 cell-mediated autoimmune diseases.

2019-08-16 | GSE72271 | GEO

Regulation of pathogenic T helper 17 cell differentiation by steroid receptor coactivator-3

Project description:T helper 17 (Th17) cell development is programmed by the orphan nuclear receptor RORgt, but the underlying mechanism is not well understood. Nuclear receptor-mediated transcriptional activation depends on coactivators. Here we show that the steroid receptor coactivator-3 (SRC-3) critically regulates Th17 cell differentiation. Reduced incidence of experimental autoimmune encephalitis (EAE) associated with decreased Th17 cell generation in vivo was observed in mice with SRC-3 deletion specifically in T cells. In vitro, SRC-3 deficiency did not affect TGF-/IL-6-induced Th17 cell generation but severely impaired pathogenic Th17 differentiation induced by IL-1/IL-6/IL-23. Microarrays were used to showed that SRC-3 not only regulates IL-17A but also IL-1R1 expression. SRC-3 bound to Il17a and Il1r1 loci in a RORtdependent manner and was required for recruitment of the p300 acetyltransferase. Thus, SRC-3 is critical in RORt-dependent gene expression during Th17 cell-driven autoimmune diseases.

2018-05-02 | GSE113927 | GEO

mRNA profiling of liver-specific RORa KO mouse liver

Project description:The retinoic acid receptor-related orphan receptor a (RORa) is a member of the NR1 subfamily of orphan nuclear hormone receptors. RORa is an important regulator of various biological processes, including cerebellum development, cancer and circadian rhythm. To determine molecular mechanism by which hepatic deletion of RORa induces obesity and insulin resistance, we performed global transcriptome analysis from high-fat diet (HFD)-fed RORa f/f and RORa LKO mouse liver tissues. This analysis provides insight into molecular mechanisms for RORa in high-fat-diet condition.

2017-06-28 | GSE83338 | GEO

Chemical Inhibition of the ROR?t-dependent Transcriptional Network in Th17 cells [RNA-Seq]

Project description:ROR?t is a transcription factor required for T helper 17 (Th17) cell development. We identified three ROR?t-specific inhibitors that suppress Th17 cell responses including Th17 cell-mediated autoimmune disease. We systemically characterized ROR?t binding data in the presence and absence of drug with corresponding whole-transcriptome sequencing for wild-type and ROR?t-deficient cells. ROR?t 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 ROR?t 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 ROR?t, DMSO, and knockout of ROR?t

2014-04-17 | E-GEOD-56018 | biostudies-arrayexpress

Decoupling the role of RORγt in the differentiation and effector function of Th17 cells

Project description:RORgt is known to instruct the differentiation of Th17 cells that mediate the pathogenesis of autoimmune diseases. However, it remains unknown whether RORgt plays a distinct role in the differentiation and effector function of Th17 cells. Here we show that mutation of RORgt lysine 256, a ubiquitination site, to arginine (K256R) separates the RORgt role in these two functions. Preventing ubiquitination at K256 via arginine substitution does not affect RORgt-dependent thymocyte development and Th17 differentiation in vitro and in vivo, however, greatly impaired the pathogenesis of Th17 cell-mediated experimental autoimmune encephalomyelitis (EAE). Mechanistically, K256R mutation impairs RORgt to bind to and activate Runx1 expression critical for Th17-mediated EAE. Thus, RORgt regulates the effector function of Th17 cells in addition to Th17 differentiation. This work informs the development of RORgt-based therapies that specifically target the effector function of Th17 cells responsible for autoimmunity.

2022-10-26 | GSE211414 | GEO

Decoupling the role of RORgt in the differentiation and effector function of Th17 cells

2022-10-26 | GSE211509 | GEO

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