Crossing Gene Sets From GTEx, Metabolomics and RummaGEO Reveals Rosiglitazone As a Potential Modulator of Cardiac Aging and Metabolic Regulation

Abstract

Biomedical omics resources are often treated as separate datasets, which fragments insight and limits discov- ery of shared mechanisms. Crossing resources generated by the NIH Common Fund through the Common Fund Data Ecosystem enables integration of experimental contexts and identification of robust molecular programs. In this report we combined three gene set libraries derived from the GTEx Tissue Specific Aging Signatures, the Metabolomics Metabolite Enzyme Associations, and the RummaGEO Drug Perturbation Sig- natures. The GTEx heart down signature captures genes whose expression declines in older heart tissue, the metabolomics acetylCoA signature groups enzymes that interact with the metabolite acetylCoA, and the RummaGEO rosiglitazone up signature reflects genes induced by rosiglitazone treatment in mouse tissue. All possible triples of gene sets were crossed and the top ranked intersection was selected because it contained the maximal number of genes shared across all sets. The resulting six gene intersection, comprising ACAA2, ACAT1, DLAT, DLD, HADHB and PDHA1, represents core mitochondrial enzymes that generate acetylCoA from fatty acids and pyruvate. Enrichment analysis highlighted central carbon and lipid metabolism pathways and transcription factors such as PPARG, suggesting that the rosiglitazone response may modulate this metabolic hub. The findings propose that targeting this hub with rosiglitazone could counteract age related declines in cardiac metabolism and restore coordinated acetylCoA production.