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MicroRNA-130a and miR-212 disrupt the intestinal epithelial barrier through modulation of peroxisome proliferator-activated receptor gamma and occludin expression in chronic SIV-infected rhesus macaques

ABSTRACT: MicroRNA-130a and miR-212 disrupt the intestinal epithelial barrier through modulation of peroxisome proliferator-activated receptor gamma and occludin expression in chronic SIV-infected rhesus macaques

PROVIDER: PRJNA413791 | ENA |

REPOSITORIES: ENA

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Bladder cancer associated mutations in RXRA activate peroxisome proliferator-activated receptors

Project description:Bladder cancer associated mutations in RXRA activate peroxisome proliferator-activated receptors

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The peroxisome proliferator-activated receptor-gamma agonist pioglitazone modulates aberrant T cell responses in systemic lupus erythematosus

Project description:Previous studies indicate that peroxisome proliferator-activated receptor-gamma (PPAR-g) agonists suppress autoimmune responses and renal inflammation in murine lupus. However, the mechanisms implicated in this process remain unclear. We tested the effect of the PPAR-g agonist pioglitazone in human lupus and control PBMCs with regards to gene regulation and various functional assays. We used microarrays to analyze the effect of Pioglitazone on peripheral blood cells (PBMCs) from healthy and lupus patients.

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MicroRNA-130a and miR-212 disrupt the intestinal epithelial barrier through modulation of peroxisome proliferator-activated receptor gamma and occludin expression in chronic SIV-infected rhesus macaques

Project description:We profiled and characterized mRNA expression exclusively in colonic epithelium (CE) of 4 chronically SIV-infected and 4 control rhesus macaques (RMs). Further analysis identified significant dowregulation of genes Genes associated with ion transport, epithelial barrier integrity/function, protection against oxidative injury, double stranded DNA damage repair and autophagy. Similarly, mRNA expression of genes associated with interferon response, anti-microbial defense, apoptosis, oxidative DNA damage, endoplasmic reticulum stress and inflammasome signaling were markedly upregulated.

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miRNA profiling of Macaca mulatta colonic epithelium samples from chronic SIV infected rhesus macaques

Project description:The study describes miRNA expression in colonic epithelium of chronic SIV-infected rhesus macaques. We profiled and characterized miRNA/mRNA expression exclusively in colonic epithelium (CE) of 12 chronically SIV-infected and 8 control rhesus macaques (RMs). About 46 miRNAs were differentially expressed (DE) (20-up and 26-down) in CE during chronic SIV infection. Using TargetScan, we bioinformatically crossed the predicted targets of DE miRNAs to genome-wide transcriptomic data and identified several critical miRNA-mRNA pairings that suggested miRNA-mediated regulation of aberrant epithelial gene expression in CE. Immunofluorescence, luciferase reporter and miRNA overexpression studies confirmed the ability of miR-130a and miR-212 to bind the 3’ UTR and downregulate protein expression of occludin (OCLN) and peroxisome proliferator activator receptor gamma (PPAR), respectively, two proteins with pivotal roles in epithelial barrier function. MiR-130a and miR-212 overexpression in Caco-2 cells significantly reduced transepithelial electrical resistance (TEER). Interestingly, delta-9-tetrahydrocannabinol (9-THC) treatment restored TEER to levels observed with control miRNA mimic. Finally, ex-vivo 9-THC treatment of colon tissue from chronically SIV-infected RMs significantly increased PPAR gene expression. Our findings suggest that dysregulated miR-130a and miR-212 expression in CE during chronic HIV/SIV infection can facilitate epithelial barrier disruption by downregulating OCLN and PPAR protein expression. Most importantly, our results highlight the beneficial effects of cannabinoids on epithelial barrier function in not just HIV/SIV but potentially other chronic intestinal inflammatory diseases.

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Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation

Project description:Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation

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Bladder Cancer Associated Mutations in RXRA activate Peroxisome Proliferator-Activated Receptors to Drive Urothelial Proliferation

Project description:Bladder Cancer Associated Mutations in RXRA activate Peroxisome Proliferator-Activated Receptors to Drive Urothelial Proliferation

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Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation

Project description:RXRA regulates transcription as part of a heterodimer with 14 other nuclear receptors, including the peroxisome proliferator-activated receptors (PPARs). Analysis from the TCGA raised the possibility that hyperactive PPAR signaling, either due to PPAR gamma gene amplification or RXRA hot-spot mutation (S427F/Y) drives 20-25% of bladder cancers. Here we characterize mutant RXRA, demonstrating it induces enhancer/promoter activity in the context of RXRA/PPAR heterodimers. Structure-function studies indicate the RXRA substitution allosterically regulates the PPAR AF2 domain via an aromatic interaction with the terminal tyrosine found in PPARs. In urothelium, we find PPAR agonism is sufficient to drive growth factor independent growth, but only after deletion of the tumor suppressors Kdm6a and Trp53. Similarly, mutant RXRA stimulates growth factor independent growth, in a manner reversible by PPAR inhibition. These studies reveal a pro-tumorigenic interaction between loss of tumor suppressors and PPAR activation and implicate PPARs as targetable drivers of bladder cancer.

2017-12-07 | GSE107735 | GEO

Bladder Cancer Associated Mutations in RXRA activate Peroxisome Proliferator-Activated Receptors to Drive Urothelial Proliferation

2017-12-07 | GSE107734 | GEO

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