Overexpression of RORA in primary mouse in vitro Th2
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 2500
ORGANISM(S): Mus musculus
SUBMITTER: Liora Haim-Vilmovsky
PROVIDER: E-MTAB-8001 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:In this expriment, Nave T cells were isolated from both RORA knockout mice and wild type mice and were differentiated towards Th2. RNA was isulated from those cells 4 days after, to identify genes that might be regulated by RORA.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/
2015-11-03 | E-ERAD-411 | biostudies-arrayexpress
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.
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Project description:Overexpression of RORA in primary mouse in vitro Th2
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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
Project description:RORasg/sg mice have small cardiomyocytes and hypocontractile hearts with increased fibrosis. Microarrays revealed broad deficits of sarcomeric RNAs and key myogenic transcription factors, suggesting that the loss of RORa leads to impaired developmental hypertrophy through transcriptional regulation. RORasg/sg mice developed exaggerated ventricular remodeling in response to Agn II infusion. We identify novel cardioprotective roles for RORa in promoting developmental and preventing pathological cardiac hypertrophy, mediated in part through regulation of the IL-6-STAT3 pathway in cardiomyocytes and cardiac fibrosis
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Project description:Background: We have recently identified the nuclear hormone receptor RORA (retinoic acid-related orphan receptor-alpha) as a novel candidate gene for autism spectrum disorder (ASD). Our independent cohort studies have consistently demonstrated the reduction of RORA transcript and/or protein levels in blood-derived lymphoblasts as well as the postmortem prefrontal cortex and cerebellum of individuals with ASD. Moreover, we have also shown that RORA has the potential to be under negative and positive regulation by androgen and estrogen, respectively, suggesting the possibility that RORA may contribute to the male bias of ASD. However, little is known about transcriptional targets of this nuclear receptor, particularly in humans. Methods: Here we comprehensively identify transcriptional targets of RORA in human neuronal cells using chromatin immunoprecipitation (ChIP), followed by whole-genome promoter array (chip) analysis. Selected potential targets of RORA were then further validated by an independent chromatin immunoprecipitation, followed by qPCR analysis. To further demonstrate that reduced RORA expression results in aberrant transcription of RORA targets, we determined the expression levels of selected transcriptional targets in RORA-deficient human neuronal cells, as well as in postmortem brain tissues from individuals with ASD who exhibit reduced RORA expression. Results: The ChIP-on-chip analysis reveals that RORA1, a major isoform of RORA protein in human brain, can be recruited to as many as 1,338 genomic locations corresponding to promoter regions of 1,274 genes across the human genome. Among the genes potentially directly regulated by RORA1 are genes known to have biological functions negatively impacted in individuals with ASD, including neuronal adhesion and survival, synaptogenesis, and development of the cortex and the cerebellum. Independent ChIP-qPCR analyses confirm binding of RORA1 to promoter regions of several ASD-associated genes, including A2BP1, CYP19A1, HSD17B10, ITPR1, NLGN1, and NTRK2, whose expression levels are also decreased in RORA1-repressed human neuronal cells and in prefrontal cortex tissues from individuals with ASD. Conclusion: Findings from this study indicate that RORA transcriptionally regulates A2BP1, CYP19A1, HSD17B10, ITPR1, NLGN1, and NTRK2, and strongly suggest that reduction of this sex hormone-sensitive nuclear receptor in the brain causes dysregulated expression of these genes which, in turn, may contribute to the underlying pathobiology of ASD. Nuclear lysates from the human neuroblastoma cell line SH-SY5Y were chromatin-immunoprecipitated with goat anti-RORA1 antibody vs. normal goat IgG antibody
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Project description:Background: We have recently identified the nuclear hormone receptor RORA (retinoic acid-related orphan receptor-alpha) as a novel candidate gene for autism spectrum disorder (ASD). Our independent cohort studies have consistently demonstrated the reduction of RORA transcript and/or protein levels in blood-derived lymphoblasts as well as the postmortem prefrontal cortex and cerebellum of individuals with ASD. Moreover, we have also shown that RORA has the potential to be under negative and positive regulation by androgen and estrogen, respectively, suggesting the possibility that RORA may contribute to the male bias of ASD. However, little is known about transcriptional targets of this nuclear receptor, particularly in humans. Methods: Here we comprehensively identify transcriptional targets of RORA in human neuronal cells using chromatin immunoprecipitation (ChIP), followed by whole-genome promoter array (chip) analysis. Selected potential targets of RORA were then further validated by an independent chromatin immunoprecipitation, followed by qPCR analysis. To further demonstrate that reduced RORA expression results in aberrant transcription of RORA targets, we determined the expression levels of selected transcriptional targets in RORA-deficient human neuronal cells, as well as in postmortem brain tissues from individuals with ASD who exhibit reduced RORA expression. Results: The ChIP-on-chip analysis reveals that RORA1, a major isoform of RORA protein in human brain, can be recruited to as many as 1,338 genomic locations corresponding to promoter regions of 1,274 genes across the human genome. Among the genes potentially directly regulated by RORA1 are genes known to have biological functions negatively impacted in individuals with ASD, including neuronal adhesion and survival, synaptogenesis, and development of the cortex and the cerebellum. Independent ChIP-qPCR analyses confirm binding of RORA1 to promoter regions of several ASD-associated genes, including A2BP1, CYP19A1, HSD17B10, ITPR1, NLGN1, and NTRK2, whose expression levels are also decreased in RORA1-repressed human neuronal cells and in prefrontal cortex tissues from individuals with ASD. Conclusion: Findings from this study indicate that RORA transcriptionally regulates A2BP1, CYP19A1, HSD17B10, ITPR1, NLGN1, and NTRK2, and strongly suggest that reduction of this sex hormone-sensitive nuclear receptor in the brain causes dysregulated expression of these genes which, in turn, may contribute to the underlying pathobiology of ASD.
2013-05-31 | GSE45756 | GEO
Project description:Proper differentiation of corneal epithelial cells (CECs) from limbal stem/progenitor cells (LSCs) is required for maintaining ocular homeostasis and clear vision. Here, using a single-cell transcriptomic atlas, we delineate the comprehensive and refined molecular regulatory dynamics during human CEC development and differentiation. We find that RORA is a CEC-specific molecular switch that initiates and drives LSCs to differentiate into mature CECs by activating PITX1. RORA dictates CEC differentiation by establishing CEC-specific enhancers and chromatin interactions between CEC gene promoters and distal regulatory elements. Conversely, RORA silences LSC-specific promoters and disrupts promoter-anchored chromatin loops to turn off LSC genes. Collectively, our work provides detailed and comprehensive insights into the transcriptional dynamics and RORA-mediated epigenetic remodeling underlying human corneal epithelial differentiation.
2023-12-04 | GSE248926 | GEO