Crossing Gene Sets From LINCS, Metabolomics and MoTrPAC Reveals FAD As a Potential Modulator of Metabolic Redox Activity and Exercise Induced Brown Adipose Regulation

Abstract

Biomedical omics resources are often treated as separate datasets, which fragments insight and limits dis- covery of shared molecular mechanisms. To overcome this limitation we leveraged three Common Fund resourcesthe LINCS L1000 CRISPR knockout perturbation signatures, the Metabolomics metaboliteenzyme association library, and the MoTrPAC rat endurance exercise transcriptomics collectionby converting each into geneset libraries via the Common Fund Data Ecosystem. We focused on a single threeway crossing that combined the URB2::BICR6 knockout signature, the flavin adenine dinucleotide (FAD) enzyme signature, and the T69 brownadipose male 8week downregulated signature, because this intersection contained the greatest number of genes shared across all possible overlaps. The resulting intersecting set comprised four mitochondrial enzymesACADM, ACADVL, GCDH and IVDeach appearing in all three source gene sets, indicat- ing maximal inclusion and a robust common signal. Enrichment analysis highlighted coordinated fattyacid betaoxidation, branchedchain aminoacid catabolism, PPAR signaling and transcriptionfactor activity of E2F1 and RUNX2, underscoring a shared role in mitochondrial energy homeostasis. These findings illustrate how crossing multiple Common Fund datasets can reveal coherent metabolic programs and prioritize biologically meaningful gene sets for further investigation.