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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE72271 | GEO | 2019/08/16

REPOSITORIES: GEO

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REV-ERBa regulates TH17 cell development and autoimmunity

Project description:RORγt is well recognized as the lineage defining transcription factor for TH17 cell development. However, the cell-intrinsic mechanisms that negatively regulate TH17 cell development and autoimmunity remain poorly understood. Here we demonstrate that the transcriptional repressor REV-ERBa is exclusively expressed in TH17 cells, competes with RORγt for their shared DNA consensus sequence, and negatively regulates TH17 cell development via repression of genes traditionally characterized as RORγt-dependent, including Il17a. Deletion of REV-ERBa enhanced TH17-mediated pro-inflammatory cytokine expression, exacerbating experimental autoimmune encephalomyelitis (EAE) and colitis. Treatment with REV-ERB-specific synthetic ligands, which have similar phenotypic properties as RORγ modulators, suppressed TH17 cell development, was effective in colitis intervention studies, and significantly decreased the onset, severity, and relapse rate in several models of EAE without affecting thymic cellularity. Our results establish that REV-ERBa negatively regulates pro-inflammatory TH17 responses in vivo and identifies the REV-ERBs as potential targets for the treatment of TH17-mediated autoimmune diseases.

2018-12-19 | GSE122726 | GEO

REV-ERBa and REV-ERBb function as key factors regulating Mammalian Circadian Output

Project description:The circadian clock regulates behavioural and physiological processes in a 24-h cycle. The nuclear receptors REV-ERBa and REV-ERBb are involved in the cell-autonomous circadian transcriptional/translational feedback loops as transcriptional repressors. A number of studies have also demonstrated a pivotal role of REV-ERBs in regulation of metabolic, neuronal, and inflammatory functions including bile acid metabolism, lipid metabolism, and production of inflammatory cytokines. Given the multifunctional role of REV-ERBs, it is important to elucidate the mechanism through which REV-ERBs exert their functions. To this end, we established a Rev-erba/Rev-erbb double-knockout mouse embryonic stem (ES) cell model and analyzed the circadian clock and clock-controlled output gene expressions. A comprehensive mRNA-seq analysis revealed that the complete knockout of both Rev-erba and Rev-erbb does not abrogate expression rhythms of E-box-regulated core clock genes but drastically changes a diverse set of other rhythmically-expressed output genes. Of note, REV-ERBa/b deficiency does not compromise circadian expression rhythms of PER2, while REV-ERB target genes, Bmal1 and Npas2, are significantly upregulated. This study emphasizes REV-ERBs function to form an essential link between the circadian clock and a wide variety of cellular physiological functions.

2019-07-29 | GSE125696 | GEO

Decoupling the role of RORgt 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 | GSE211509 | GEO

REV-ERBa regulates TH17 cell development and autoimmunity

Project description:REV-ERBa regulates TH17 cell development and autoimmunity

| PRJNA506082 | ENA

Discrete Functions of Rev-erba Couple Metabolism to the Clock [HTS]

Project description:Circadian and metabolic physiology are intricately intertwined, as illustrated by Rev-erb , a transcription factor (TF) that functions both as a core repressive component of the cell autonomous clock and as a regulator of metabolic genes. Here we show that Rev-erb modulates the clock and metabolism by different genomic mechanisms. Clock control requires Rev-erb to bind directly to the genome at its cognate sites, where it competes with activating ROR TFs. By contrast, Rev-erb regulates metabolic genes primarily by recruiting the HDAC3 corepressor to sites to which it is tethered by cell type-specific transcription factors. Thus, direct competition between Rev-erb and ROR TFs provides a universal mechanism for self-sustained control of molecular clock across all tissues, whereas Rev-erb utilizes lineage-determining factors to convey a tissue-specific epigenomic rhythm that regulates metabolism tailored to the specific need of that tissue.

2015-06-16 | GSE67962 | GEO

Discrete Functions of Rev-erba Couple Metabolism to the Clock [array]

2015-06-16 | GSE67964 | GEO

Discrete Functions of Rev-erba Couple Metabolism to the Clock [HTS]

2015-06-16 | E-GEOD-67962 | biostudies-arrayexpress

HNF6 and Rev-erba Integrate Hepatic Lipid Metabolism By Overlapping and Distinct Transcriptional Mechanisms [ChIP-Seq]

Project description:We address the function of HNF6 in the mouse liver metabolism and Rev-erba cistrome We performed Rev-erba ChIP-seq in mouse livers at 5pm of the day and compared between WT and HNF6-depleted livers.

2016-06-29 | E-GEOD-83790 | biostudies-arrayexpress

Discrete Functions of Rev-erba Couple Metabolism to the Clock [array]

2015-06-16 | E-GEOD-67964 | biostudies-arrayexpress

Next Generation Sequencing Facilitates Quantitative Analysis of RNAs bound by DDX5 and RORgt in cultured T helper 17 cell [RIP-seq]

Project description:Purpose: The goals of this study are to compare RNAs bound by DDX5 and RORgt in cultured T helper 17 cell in wildtype background. Methods: Th17 mRNA profiles of 48hrs in vitro cultured T helper 17 cells from wild-type mice were generated by deep sequencing, using Illumina HighSeq. The sequence reads that passed quality filters were analyzed at the transcript isoform level with two methods: BurrowsâWheeler Aligner (BWA) and TopHat followed by CuffDiff. qRTâPCR validation was performed using SYBR Green assays. Results: Among the 3444 RefSeq non-coding RNAs and 46449 NONCODE non-coding RNAs, 2533 were found to be expressed in Th17 cells (FPKM>1). 210 of them were enriched in DDX5 pull-down and 119 of them were enriched in RORgt pull-down. Conclusions: Our study suggest that a subset of 31 ncRNAs were co-enriched in DDX5 and RORgt pull-down. DDX5 or RORgt-associated-RNA profiles of 48hr in vitro cultured Th17 from wild type (WT) mice were generated by deep sequencing using Illumina HighSeq

2015-12-21 | E-GEOD-70109 | biostudies-arrayexpress

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