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Dynamic complexity of genetic regulatory effects in response to a high cholesterol, high fat diet in baboons

ABSTRACT: Dynamic complexity of genetic regulatory effects in response to a high cholesterol, high fat diet in baboons

PROVIDER: PRJNA944682 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23866100_1.fastq.gz	Fastqsanger.gz
	SRR23866100_2.fastq.gz	Fastqsanger.gz
	SRR23866200.fastq.gz	Fastqsanger.gz
	SRR23866300_1.fastq.gz	Fastqsanger.gz
	SRR23866300_2.fastq.gz	Fastqsanger.gz

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Differential microRNA response to a high-cholesterol, high-fat diet in livers of low and high LDL-C baboons

Project description:Dysregulation of microRNAs (miRNAs) expression has been implicated in molecular genetics events leading to the progression and development of atherosclerosis. We hypothesized that miRNA expression profiles differ between baboons with low and high serum low-density lipoprotein cholesterol (LDL-C) concentrations in response to diet, and that a subset of these miRNAs regulate genes relevant to dyslipidemia and risk of atherosclerosis. We generated small RNA libraries from baboons differing in their LDL-C response to dietary fat and cholesterol (low LDL-C, n = 3; high LDL-C, n = 3) using liver biopsies collected before and after a high-cholesterol, high-fat (HCHF) challenge diet. We sequenced the libraries using Next-Generation Illumina sequencing methods, analyzed the data using mirTools software and identified 517 baboon miRNAs: 490 homologous to human and 27 novel miRNAs. HCHF diet elicited expression of more miRNAs compared to baseline (chow) diet for both low and high LDL-C baboons. Seventeen miRNAs exhibited significant differential expression in response to HCHF diet in high LDL-C baboons compared to nine miRNAs in low LDL-C baboons. Putative miRNA targets were identified with TargetScan/Base tools. miRNAs significantly targeted more genes in high LDL-C baboons compared to low LDL-C responders. Further, we identified miRNA isomers and other non-coding RNAs that were differentially expressed in response to the challenge diet.Our discovery of differentially expressed baboon miRNAs and their targets is a fundamental step in understanding the role of non-coding RNAs in the modulation of dsylipidemia.

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Dynamic complexity of genetic regulatory effects in response to a high cholesterol, high fat diet in baboons

Project description:Steady-state expression quantitative trait loci (eQTLs) explain only a fraction of disease-associated loci identified through genome-wide association studies (GWAS), while eQTLs involved in gene-by-environment (GxE) interactions have rarely been characterized in humans due to experimental challenges. Using a baboon model, we found hundreds of eQTLs that emerge in adipose, liver, and muscle after prolonged exposure to high dietary fat and cholesterol. Diet-responsive eQTLs exhibit genomic localization and genic features that are distinct from steady-state eQTLs. Furthermore, the human orthologs associated with diet-responsive eQTLs are enriched for GWAS genes associated with human metabolic traits, suggesting that context-responsive eQTLs with more complex regulatory effects are likely to explain GWAS hits that do not seem to overlap with standard eQTLs. Our results highlight the complexity of genetic regulatory effects and the potential of eQTLs with disease-relevant GxE interactions in enhancing the understanding of GWAS signals for human complex disease using nonhuman primate models.

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Project description:Analysis of hepatic transcript data using unbiased Weighted Gene Correlation Network Analysis (WGCNA) to identify significant modules of genes correlated with lesion burden and performed pathway enrichment analysis of genes in significant modules. The hypothesis tested in the present study was that transcript modules are predictive of atherosclerotic lesion burden after a high cholesterol, high fat diet challenge. results of the study provide an understanding of the key pathways and genes underlying atherosclerotic lesion burdenafter high cholesterol and high fat diet challenge in baboons .

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Hepatic transcript modules are predictive of atherosclerotic lesion burden after a 2-year high cholesterol, high fat diet challenge in baboons

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