Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Natural variation of histone modification and its impact on gene expression in rat

ABSTRACT: Histone modifications are epigenetic marks that play fundamental roles in many biological processes including the control of chromatin-mediated regulation of gene expression. To begin to understand the impact of natural variation on histone methylation levels we generated and quantified large-scale genome-wide ChIP-seq data in a panel of rat recombinant inbred strains and their parental progenitors. Linkage analysis identified hundreds of cis- and trans-acting loci responsible for quantitative differences in histone trimethyl-lysine levels in left ventricular heart and liver tissues. We assessed the association of histone methylation and gene expression levels by generating deep RNA-seq profiles across the segregating population. Among the main findings, causal modelling of DNA variation together with histone methylation and gene expression levels enhanced the prediction of gene expression traits (eQTLs) by ~20%. Moreover, allele specific differences of histone trimethyl-lysine levels at alternative promoters were associated with differential usage of transcriptional start sites. Our data suggest that genetic variation has widespread impact on histone modifications. The highly adapted interplay between DNA variation and chromatin structure has consequences on gene and isoform expression as direct functional outcome and demonstrated new avenues to find novel genotype Ð phenotype relationships. NOTE: Additional processed data files were added to this experiment on the 24th April 2014. They are in the zip archive E-MTAB-1102.additional.1.zip which is available under the 'Click to browse all available files' link.

ORGANISM(S): Rattus norvegicus

SUBMITTER: Oliver Hummel

PROVIDER: E-MTAB-1102 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Metabolic syndrome is associated with chronic low-grade inflammation which plays an important role in the pathogenesis of insulin resistance. Salsalate is a non-steroidal anti-inflammatory drug that reduces levels of inflammatory mediators. In the current study, we tested the effects of salsalate on inflammation, oxidative stress and metabolic disturbances in an animal model of inflammation and metabolic syndrome, using spontaneously hypertensive rats that transgenically express human C-reactive protein (SHR-CRP). We treated 15-month-old male transgenic SHR-CRP rats with salsalate (200 mg/kg/day) mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP rats were fed a standard diet without salsalate. In a similar fashion, we studied a group of nontransgenic SHR treated with salsalate and an untreated group of nontransgenic SHR controls. Parameters of inflammation and glucose and lipid metabolism were measured using standard methods. Statistical significance was evaluated by two-way ANOVA. In the SHR-CRP transgenic strain, we found that salsalate treatment decreased circulating levels of inflammatory markers TNFï¡ and MCP-1 and levels of human CRP as well as reduced levels of lipopreroxidation products in the liver and kidney cortex. Lipidomics analysis of eicosanoids confirmed anti-inflammatory effects of salsalate. Reduced inflammation and oxidative stress were associated with increased sensitivity of skeletal muscles to insulin action and greater tolerance to glucose and with reduced glucose oxidation and incorporation in brown adipose tissue (BAT). In SHR controls with no CRP-induced inflammation, salsalate treatment was associated with reduced body weight, lower levels of serum free fatty acids, total and HDL cholesterol and increased palmitate oxidation and incorporation in BAT. Salsalate regulated lipid metabolism by affecting expression of genes from PPAR signaling pathways and inflammation by affecting expression from MAPK signaling and NOD-like receptor signaling pathways. In summary, in the presence of high levels of human CRP, salsalate reduced inflammation which was associated with reduced oxidative stress and amelioration of insulin resistance in skeletal muscle and glucose intolerance while in non-transgenic SHR rats, salsalate ameliorated dyslipidemia and activated BAT. Thus it is possible that amelioration of insulin resistance and glucose intolerance in SHR-CRP rats treated with salsalate is due to reduced inflammation while amelioration of dyslipidemia in SHR rats treated with salsalate is due to activation of BAT. These findings suggest that salsalate has metabolic effects beyond suppressing inflammation.

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Natural variation of histone modification and its impact on gene expression in rat

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