RORα is crucial for attenuated inflammatory response to maintain intestinal homeostasis.
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ABSTRACT:
PROVIDER: PRJNA501886 | ENA |
REPOSITORIES: ENA
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Project description:Retinoic acid-related orphan receptor α (RORα) functions as a transcription factor for various biological processes, including circadian rhythm, cancer, and metabolism. Here, we generate intestinal epithelial cell (IEC)-specific RORα-deficient (RORαΔIEC) mice and find that RORα is crucial for maintaining intestinal homeostasis by attenuating nuclear factor κB (NF-κB) transcriptional activity. RORαΔIEC mice exhibit excessive intestinal inflammation and highly activated inflammatory responses in the dextran sulfate sodium (DSS) mouse colitis model. Transcriptome analysis reveals that deletion of RORα leads to up-regulation of NF-κB target genes in IECs. Chromatin immunoprecipitation analysis reveals corecruitment of RORα and histone deacetylase 3 (HDAC3) on NF-κB target promoters and subsequent dismissal of CREB binding protein (CBP) and bromodomain-containing protein 4 (BRD4) for transcriptional repression. Together, we demonstrate that RORα/HDAC3-mediated attenuation of NF-κB signaling controls the balance of inflammatory responses, and therapeutic strategies targeting this epigenetic regulation could be beneficial to the treatment of chronic inflammatory diseases, including inflammatory bowel disease (IBD).
| S-EPMC6800319 | biostudies-literature
Project description:A member of the nuclear receptors, retinoic acid-related orphan receptor a (RORa) is an important transcription factor for various biological processes including circadian rhythm, metabolic regulation, immune cell development and cancer. Here we found that RORa is important for intestinal homeostasis by negatively regulating the transcriptional activity of NF-kB, a major inflammatory regulator in intestinal epithelial cells. Intestinal Rora-deficient mice found were highly susceptible to DSS-induced injury. Transcriptome analysis showed that intestine-specific Rora deletion causes regulatory impairment of NF-kB signaling leading to excessive inflammatory responses. RORa specifically binds to the NF-kB target promoter and inhibits transcriptional activity for transcriptional repression of NF-kB activity via histone deacetylase 3 (HDAC3). Taken together, RORa plays a pivotal role in the homeostatic regulation of intestinal epithelial cells in inflammatory conditions. Therefore, therapeutic strategies designed to modulate RORa activity may be beneficial in the treatment of chronic inflammatory diseases such as Inflammatory bowel disease (IBD).
2019-09-30 | GSE121977 | GEO
Project description:Osteoarthritis is characterized by cartilage destruction, chronic inflammation, and subchondral sclerosis. Evidence showed that nuclear receptor family is closely associated with cartilage damage in an unclear molecular mechanism. Here, we investigated the role and molecular mechanism of the retinoic acid receptor-related orphan receptor-α (RORα), an important member of nuclear receptor, in regulating cartilage degradation and osteoarthritis pathogenesis. Investigation to osteoarthritis clinical specimen showed that the degree of RORα elevation is positively correlated with the severity of osteoarthritis and cartilage damage. In an in vivo osteoarthritis models induced by anterior crucial ligament transaction, intraarticularly injection of siRora adenovirus reversed the cartilage damage. RORα knock-down increased the protein expression level of anabolic factor such as type II collagen, Aggrecan, and decreased the expression of catabolic factor. RNA-seq data suggested IL-6/STAT3 pathway is significantly down-regulated. Mechanistically, RORα knock-down decreased the expression level of both IL-6 and phosphorylated STAT3. RORα exerted its effect on IL-6/STAT3 signaling in two different ways, which includes interaction with STAT3 and IL6 promoter. Taken together, our findings indicated the pivotal role of RORα/IL-6/STAT3 axis in osteoarthritis progression and confirmed RORα knock-down exerted therapeutic effect in human chondrocyte thus providing a potential drug target in osteoarthritis therapy.
2021-04-20 | GSE172291 | GEO
Project description:Purpose: To identify the target genes of RORα associated with development of NASH Methods: RNA isolation for sequencing analysis from liver tissues of High fat diet (HFD)-fed RORα-LKO and RORα f/f mice and mRNA-sequencing Conclusion: When calcuated by dividing the normalized read count of HFD-fed RORα-LKO by that of RORαf/f,.there are 8505 genes altered by RORα deletion (cut-off, 0.8-fold, 1.5-fold).
2019-12-03 | GSE90844 | GEO
Project description:MrgprD-expressing neurons maintain cutaneous mast cell homeostasis
| PRJNA600963 | ENA
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| PRJNA771642 | ENA
Project description:GTPBP1 resolves paused ribosomes to maintain neuronal homeostasis
| PRJNA663319 | ENA
Project description:In an effort to study gene expression modulated by RORɣt and RORα in human Th17 cells, global gene expression of human CD4 T cells activated under Th17 skewing conditions was profiled by RNA sequencing. RORɣt and RORα signature genes were identified in these Th17 cells treated with specific siRNAs to knock down RORɣt or RORα expression. In addition, selective small molecule RORɣt modulators were also utilized as pharmacological tools in RORɣt signature gene identification.
2017-09-14 | GSE103844 | GEO
Project description:The molecular interplay between miRNA and mRNA is critical for tumorigenesis, whereas it is not comprehensively profiled in OSCC. Here, we aimed to explore the potential network of miRNAs-mediated genes. Furthermore, the cooperative effect of miRNAs on RORα in tumor proliferation was elucidated. Four pairs of cancer and adjacent normal tissues were collected for high-throughput sequencing. The regulatory interactions between differentially expressed miRNAs and mRNAs were performed by bioinformatics analysis. Luciferase reporter assay and qRT-PCR assay were used to examine the effects of miRNAs on RORα. The CCK8 assay and mice xenografts assay were used to assess the role of RORα on OSCC proliferation in vitro and in vivo. Western blotting was used to detect the total and phosphorylated p53 protein level in cells with enforced or suppressed RORα expression.Differentially expressed mRNAs and miRNAs between paired OSCC and normal tissues were identified. The negative correlation networks between the up-regulated miRNA and down-regulated transcription factors (TFs) were determined. Five miRNAs (miR-503-5p, miR-450b-5p, miR-27a-3p, miR-181a-5p, miR-183-5p) were testified to directly target RORα, and resulted in a more stronger effect on RORα suppression by mixing together. In addition, RORα was detected to be generally decreased in 44 OSCC samples and significantly suppressed the proliferation of OSCC cells in vitro and in vivo. Attenuated RORα decreased p53 protein expression and suppressed p53 phosphorylation activity. The study revealed the possible miRNAs-mediated TFs network in OSCC and identified the cooperative miRNAs effect on RORα expression in OSCC proliferation.
2019-10-28 | GSE107445 | GEO
Project description:BMPR2 Regulates Hypoxic Exosome Signaling to Maintain Vascular Homeostasis
| PRJNA660478 | ENA