Correlation guided Network Integration (CoNI) reveals novel genes affecting hepatic metabolism
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PROVIDER: PRJNA573893 | ENA |
REPOSITORIES: ENA
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Project description:Obesity-induced ectopic fat disposition in the liver is a major risk factor in the pathogenesis of type 2 diabetes as it impairs hepatic insulin sensitivity, a crucial component of whole body glucose homeostasis; however molecular mechanisms remain largely elusive. Understanding the pathogenesis of fatty liver, including the identification of novel genetic regulators that are involved in the regulation of liver metabolism under excess energy supply, is crucial for the development and implementation of efficient prevention and treatment strategies. We here developed a new method to integrate metabolomics and transcriptomics data based on pairwise correlation analysis of metabolites coupled to partial correlation combining the metabolite correlations with the transcript expression profiles followed by the construction of undirected, weighted graphs.This Correlation based Network Integration (CoNI) approach was applied to liver metabolome and transcriptome datasets of lean and HFD-fed obese mice to unravel previously hidden local regulator genes (LRG). The selected candidate genes were validated by transcriptome-proteome correlation analysis, by association studies with liver lipid metabolism in humans and by analysis of cellular metabolite levels after siRNA knockdown. Overall, the new bioinformatic CoNI approach for Omics datasets allowed us to identify genes regulating metabolic networks in livers of obese mice that if solely analyzing the transcriptome dataset would have remained hidden.
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Project description:ObjectiveTechnological advances have brought a steady increase in the availability of various types of omics data, from genomics to metabolomics. Integrating these multi-omics data is a chance and challenge for systems biology; yet, tools to fully tap their potential remain scarce.MethodsWe present here a fully unsupervised and versatile correlation-based method - termed Correlation guided Network Integration (CoNI) - to integrate multi-omics data into a hypergraph structure that allows for the identification of effective modulators of metabolism. Our approach yields single transcripts of potential relevance that map to specific, densely connected, metabolic subgraphs or pathways.ResultsBy applying our method on transcriptomics and metabolomics data from murine livers under standard Chow or high-fat diet, we identified eleven genes with potential regulatory effects on hepatic metabolism. Five candidates, including the hepatokine INHBE, were validated in human liver biopsies to correlate with diabetes-related traits such as overweight, hepatic fat content, and insulin resistance (HOMA-IR).ConclusionOur method's successful application to an independent omics dataset confirmed that the novel CoNI framework is a transferable, entirely data-driven, flexible, and versatile tool for multiple omics data integration and interpretation.
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