Crossing Gene Sets From LINCS, Metabolomics and MoTrPAC Reveals Oxoglutaric Acid As a Potential Modulator of Energy Metabolism and Exercise Adaptation

Abstract

Biomedical omics resources are often analyzed as discrete datasets, which fragments insight and limits discov- ery of shared mechanisms. Crossing Common Fund datasets can reveal robust molecular programs, improve reproducibility, and connect perturbations to physiology. In this report we intersected three complemen- tary gene sets drawn from the LINCS L1000 CRISPR KO Perturbation Signatures library, the Metabolomics Metabolite Enzyme Associations library, and the MoTrPAC Rat Endurance Exercise Training Transcriptomics library. The LINCS set captures genes upregulated after FAM20C knockout in HT29 cells, the Metabolomics set links enzymes to the metabolite oxoglutaric acid, and the MoTrPAC set identifies genes downregulated in brown adipose tissue after eight weeks of endurance exercise. By crossing all possible one-to-one-to-one combinations we selected the top ranked overlap because it exhibited maximal inclusion of genes across the three libraries, as reflected by its very low p value despite a modest Jaccard index. The intersection contains four mitochondrial enzymes DLD, DLST, IDH2 and IDH3A that appear in every gene set, underscoring a core role for tricarboxylic acid cycle activity and redox balance. Enrichment analysis highlights central carbon metabolism, the citrate cycle, acetylCoA biosynthesis, and transcription factors such as E4F1 and HOXA2, while phenotype links include mood instability and lung cancer.