Integrative analysis of hepatic transcriptional profiles reveals genetic regulation of atherosclerosis in hyperlipidemic Diversity Outbred-F1 mice
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ABSTRACT:
PROVIDER: PRJNA742132 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14997300.fastq.gz | Fastqsanger.gz | |||
| SRR14997400.fastq.gz | Fastqsanger.gz | |||
| SRR14997500.fastq.gz | Fastqsanger.gz | |||
| SRR14997301.fastq.gz | Fastqsanger.gz | |||
| SRR14997401.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: To investigate the sex-dependence of liver transcriptome in Diversity Outbred (DO)-F1 mice Methods: Total RNA was extracted from snap-frozen liver using miRVana total RNA isolation kit (Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer’s protocol. The quality and amount of liver RNA were evaluated using a Bioanalyzer (Agilent, Inc., Santa Clara, CA). The average RNA-integrity score for 162 DO-F1 liver samples was 9.01 ± 0.4. RNA samples from 85 females and 77 males were submitted to the UC Davis DNA Technologies Core at the Genome Center. The RNA-seq libraries were constructed from 1 µg total RNA after poly-A library preparation. To minimize technical variability, all samples were assigned to each lane and the pooled libraries were sequenced on two lanes of the Illumina NovaSeq 6000 sequencing (Illumina Inc., San Diego, CA, USA) to achieve paired-end reads of at least 25 million 150 bp. Only R1 was used in the analysis and only R1 was submitted. Results: Our results demonstrate the tremendous effects of sex on hepatic gene expression. In support of this, genetic loci associated with the transcripts frequently showed sex specificity. We revealed sex-specific candidate genes that were mapped to the quantitative trait loci for aortic lesion area and whose expression was regulated locally regulated via global liver transcriptome. Conclusions: Our study provide a valuable data resource to the research community and show that liver transcriptomic analysis identified diet- or strain-specific pathways to pathogenesis of metabolic syndrome.
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Project description:Atherogenesis is an insipidus but precipitating process leading to serious consequences of many cardiovascular diseases (CVD). Numerous genetic loci contributing to atherosclerosis have been identified in human genome-wide association studies, but these studies have limitations in the ability to control environmental factors and to decipher cause/effect relationships. To assess the power of hyperlipidemic Diversity Outbred (DO) mice in facilitating quantitative trait loci (QTL) analysis of complex traits, we generated a high-resolution genetic panel of atherosclerosis susceptible (DO-F1) mouse cohort by crossing 200 DO females with C57BL/6J males carrying two human genes: encoding apolipoprotein E3-Leiden and cholesterol ester transfer protein. We examined atherosclerotic traits including plasma lipids and glucose in the 235 female and 226 male progeny before and after 16 weeks of a high-fat/cholesterol diet, and aortic plaque size at 24 weeks. We also assessed the liver transcriptome using RNA-sequencing. Our QTL mapping for atherosclerotic traits identified one previously reported female-specific QTL on Chr10 with a narrower interval of 22.73 to 30.80 Mb, and one novel male-specific QTL at 31.89 to 40.25 Mb on Chr19. Liver transcription levels of several genes within each QTL were highly correlated with the atherogenic traits. A majority of these candidates have already known atherogenic potential in humans and/or mice, but integrative QTL, eQTL, and correlation analyses further pointed Ptprk as a major candidate of the Chr10 QTL, while Pten and Cyp2c67 of the Chr19 QTL in our DO-F1 cohort. Finally, through additional analyses of RNA-seq data we identified genetic regulation of hepatic transcription factors, including Nr1h3, contributes to atherogenesis in this cohort. Thus, an integrative approach using DO-F1 mice effectively validates the influence of genetic factors on atherosclerosis in DO mice and suggests an opportunity to discover therapeutics in the setting of hyperlipidemia.
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Project description:Atherosclerosis is a progressive disease characterized by the accumulation of lipids in the large and medium sized arteries. Lipoproteins and the endothelium play critical roles in the onset of atherosclerosis through the regulation of trans-endothelial lipoprotein flux in the subintima, the expression of adhesion molecules and proinflamatory cytokine, and the recruitment of monocytic precursors to intimal macrophage foam cells. Although it has been greatly studied in animal models, including rabbits, pigs, non-human primates and rodents, the early development of atherosclerosis is unknown. In this study, we characterized the temporal changes of carotid endothelial transcriptome in hyperlipidemic pigs using next-generation RNA sequencing. Twenty litters of castrated barrows swine (Yorkshire x Landrace) were raised on a normal diet. The swine (~250 lbs) were then fed with a diet high in fat and cholesterol (HFHC) for 0, 2, 4, 8, or 12 weeks (n=4 animals for each time point) prior to tissue collections. The normal diet consisted of a standard commercial corn/soybean meal diet (18% crude protein) at 100% ad libitum intake. The isocaloric high fat/high cholesterol diet consisted of 16.5% crude protein, 15% fat and 1.5% cholesterol at 80% of the ad libitum feed rate (by weight) such that the caloric intake/kg BW were approximately the same as the control diet. Diets were adjusted biweekly according to body weight. Food was withheld for 24 hours prior to endothelium collection in order to permits the collection of blood for fasting lipid levels.
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