Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA268058 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1657960.fastq.gz | Fastqsanger.gz | |||
| SRR1657961.fastq.gz | Fastqsanger.gz | |||
| SRR1657962.fastq.gz | Fastqsanger.gz | |||
| SRR1657963.fastq.gz | Fastqsanger.gz | |||
| SRR1657964.fastq.gz | Fastqsanger.gz |
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Project description:MicroRNAs (miRNAs) are important regulators and potential therapeutic targets of metabolic disease. In this study we show by in vivo administration of locked nucleic acid (LNA) inhibitors that suppression of endogenous miR-29 lowers plasma cholesterol levels by ~40%, commensurate with the effect of statins, and reduces fatty acid content in the liver by ~20%. Whole transcriptome sequencing of the liver reveals 883 genes dysregulated (612 down, 271 up) by inhibition of miR-29. The set of 612 down-regulated genes are most significantly over-represented in lipid synthesis pathways. Among the up-regulated genes are the anti-lipogenic deacetylase sirtuin 1 (Sirt1) and the anti-lipogenic transcription factor aryl hydrocarbon receptor (Ahr), the latter of which we demonstrate is a direct target of miR-29. In vitro radiolabeled acetate incorporation assays confirm that pharmacologic inhibition of miR-29 significantly reduces de novo cholesterol and fatty acid synthesis. Our findings indicate that miR-29 controls hepatic lipogenic programs, likely in part through regulation of Ahr and Sirt1, and therefore may represent a candidate therapeutic target for metabolic disorders such as dyslipidemia. Hepatic mRNA profiles of C57BL/6J female mice treated with LNA against miR-29a, miR-29b and miR-29c versus saline.
2015-08-07 | E-GEOD-63493 | biostudies-arrayexpress
Project description:MicroRNAs (miRNAs) are important regulators and potential therapeutic targets of metabolic disease. In this study we show by in vivo administration of locked nucleic acid (LNA) inhibitors that suppression of endogenous miR-29 lowers plasma cholesterol levels by ~40%, commensurate with the effect of statins, and reduces fatty acid content in the liver by ~20%. Whole transcriptome sequencing of the liver reveals 883 genes dysregulated (612 down, 271 up) by inhibition of miR-29. The set of 612 down-regulated genes are most significantly over-represented in lipid synthesis pathways. Among the up-regulated genes are the anti-lipogenic deacetylase sirtuin 1 (Sirt1) and the anti-lipogenic transcription factor aryl hydrocarbon receptor (Ahr), the latter of which we demonstrate is a direct target of miR-29. In vitro radiolabeled acetate incorporation assays confirm that pharmacologic inhibition of miR-29 significantly reduces de novo cholesterol and fatty acid synthesis. Our findings indicate that miR-29 controls hepatic lipogenic programs, likely in part through regulation of Ahr and Sirt1, and therefore may represent a candidate therapeutic target for metabolic disorders such as dyslipidemia.
2015-08-07 | GSE63493 | GEO
Project description:We report on the characterization of lipogenic tissue transcriptional networks that support physiological responses of obese rats to a lipid-lowering bioactive food compound, R-a-lipoic acid (LA). Nine-week old male ZDF (fa/fa) rats were fed a chow diet supplemented with 3 g LA per kg diet or pair fed for two weeks. At the end of the trial, high-quality RNA was extracted from the liver and epididymal fat and subjected to transcriptome analysis using RNA-Seq technology. Results showed a substantially higher number of differentially expressed genes (DEG, q ⤠0.05 and absolute log2(fold change) ⥠1) in liver (110 genes) vs. epididymal fat (10 genes). Most epididymal fat DEG were also differentially expressed in liver and shared directionality of change. Gene Ontology (GO) analysis of these transcripts revealed significant enrichment of GO categories related to immune response, stress response, lipid metabolism, and carboxylic acid metabolic processes. Of interest interferon-related genes involved in defense against microorganism and innate immune response were induced by LA. Lipid metabolism-related transcript changes observed in LA-fed animals included downregulation of lipogenic genes (Pnpla3, Pnpla5, Elov6, Acly, Gpam, and Aacs) and concomitant upregulation of short-, medium- and long-chain fatty acid metabolic processes (Acot1, Acot2, Acsf2, and Crat). Transcriptional changes were accompanied by the lowering of abdominal adiposity and blood triacylglycerol levels. We conclude that LA dietary supplementation induces prominent gene expression changes in liver in support of significant improvement of whole-body lipid status For each tissue and feed combination (liver/LA+, liver/LA-, adipose/LA+, and adipose/LA-) the transcriptome was sequenced with 4 biological replicates.
2014-01-08 | E-GEOD-50424 | biostudies-arrayexpress
Project description:We report on the characterization of lipogenic tissue transcriptional networks that support physiological responses of obese rats to a lipid-lowering bioactive food compound, R-a-lipoic acid (LA). Nine-week old male ZDF (fa/fa) rats were fed a chow diet supplemented with 3 g LA per kg diet or pair fed for two weeks. At the end of the trial, high-quality RNA was extracted from the liver and epididymal fat and subjected to transcriptome analysis using RNA-Seq technology. Results showed a substantially higher number of differentially expressed genes (DEG, q ≤ 0.05 and absolute log2(fold change) ≥ 1) in liver (110 genes) vs. epididymal fat (10 genes). Most epididymal fat DEG were also differentially expressed in liver and shared directionality of change. Gene Ontology (GO) analysis of these transcripts revealed significant enrichment of GO categories related to immune response, stress response, lipid metabolism, and carboxylic acid metabolic processes. Of interest interferon-related genes involved in defense against microorganism and innate immune response were induced by LA. Lipid metabolism-related transcript changes observed in LA-fed animals included downregulation of lipogenic genes (Pnpla3, Pnpla5, Elov6, Acly, Gpam, and Aacs) and concomitant upregulation of short-, medium- and long-chain fatty acid metabolic processes (Acot1, Acot2, Acsf2, and Crat). Transcriptional changes were accompanied by the lowering of abdominal adiposity and blood triacylglycerol levels. We conclude that LA dietary supplementation induces prominent gene expression changes in liver in support of significant improvement of whole-body lipid status
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Project description:Overexpression and inhibition of miR-29 (pre-miR and anti-miR to miR-29b) in murine aortic smooth muscle cells, analysis of their secretome (conditioned media after serum starvation), n=3 for all four groups (pre-miR control, pre-miR-29b, anti-miR control, anti-miR-29b).
2016-05-06 | PXD003938 | Pride
Project description:Immune checkpoint inhibitors (ICI), like those that block PD-1/PD-L1, have revolutionized oncological therapy for patients with non-small cell lung cancer (NSCLC). However, most patients demonstrate no clinical benefit or acquire resistance, even in PD-L1+ populations, highlighting the critical need to dissect tumor survival dependencies to overcome resistance. Using our unique Kras/p53-driven lung cancer models which demonstrate acquired or intrinsic resistance to ICI, we performed single cell RNA-sequencing and focused on predicted upstream regulators of differentially expressed genes (DEGs) in the malignant cell cluster of resistant tumors. We found that the micro-RNA, miR-29, was downregulated in tumors with anti-PD-1 resistance, leading to significant upregulation of a multitude of miR-29 targets. Interestingly, we found that the immunosuppressive molecule Enpp2/ATX was one of these genes modulated due to miR-29 loss, and re-expression of miR-29 in anti-PD-1 resistant models diminished ATX tumor expression, diminished the fibrotic microenvironment, and increased CD8 infiltration. Additionally, analysis of lung adenocarcinoma patients revealed miR-29-high patients had increased CD8A expression and enrichment in immunoregulatory pathways. Together, these data provide evidence that the miR-29 family broadly regulates the tumor microenvironment, including anti-tumor immune-related pathways in lung cancer, through control of ATX among many other target genes, with implications in ICI response.
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Project description:HOXB13 is a prostate-specific homeodomain transcription factor that is mainly known as an androgen receptor (AR) cofactor. Recent studies have revealed AR-independent roles of HOXB13 in recruiting HDAC3 to suppress lipogenic programs in prostate cancer (PCa). As such, HOXB13 down-regulation leads to lipid accumulation and tumor metastasis, the molecular mechanisms of which, however, are incompletely understood. Here, we demonstrate that p300/CBP co-occupies HOXB13/HDAC3-repressed lipogenic enhancers and is required for their activation and target gene expression upon HOXB13 loss. We found that HOXB13 is down-regulated in metastatic hormone-sensitive PCa compared to their matched primary prostate tumors. HOXB13 loss induces matrix metalloproteinases (MMPs), which mediate HOXB13-depleted cell motility. Critically, CCS1477, a pharmacological inhibitor of p300/CBP, abolished HOXB13-loss-induced lipid accumulation, MMP gene expression, cell motility in vitro, and tumor metastasis in vivo. Taken together, our results suggest HOXB13 as a significant metastasis suppressor and identify p300/CBP as critical therapeutic targets in HOXB13-low metastatic PCa.
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Project description:HOXB13 is a prostate-specific homeodomain transcription factor that is mainly known as an androgen receptor (AR) cofactor. Recent studies have revealed AR-independent roles of HOXB13 in recruiting HDAC3 to suppress lipogenic programs in prostate cancer (PCa). As such, HOXB13 down-regulation leads to lipid accumulation and tumor metastasis, the molecular mechanisms of which, however, are incompletely understood. Here, we demonstrate that p300/CBP co-occupies HOXB13/HDAC3-repressed lipogenic enhancers and is required for their activation and target gene expression upon HOXB13 loss. We found that HOXB13 is down-regulated in metastatic hormone-sensitive PCa compared to their matched primary prostate tumors. HOXB13 loss induces matrix metalloproteinases (MMPs), which mediate HOXB13-depleted cell motility. Critically, CCS1477, a pharmacological inhibitor of p300/CBP, abolished HOXB13-loss-induced lipid accumulation, MMP gene expression, cell motility in vitro, and tumor metastasis in vivo. Taken together, our results suggest HOXB13 as a significant metastasis suppressor and identify p300/CBP as critical therapeutic targets in HOXB13-low metastatic PCa.
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