Crossing Gene Sets from GlyGen, GTEx, and LINCS Reveals SEPHS2 as a Potential Modulator of Glycosylation and Aging

Abstract

Biomedical omics resources are often treated as separate collections, which limits insight into shared biological mechanisms. To overcome this fragmentation, we crossed gene sets from three NIH Common Fund programs: the GlyGen Glycosylated Proteins library, which supplies curated sets of proteins modified by glycans; the GTEx TissueSpecific Aging Signatures, which capture genes upregulated in spleen tissue of older adults; and the LINCS L1000 CRISPR KO Perturbation Signatures, which provide genes downregulated after SEPHS2 knockout in A375 cells. By systematically evaluating all possible threeway combinations and selecting the crossing with the strongest statistical support and maximal gene inclusion, we identified a single intersection of fourteen genes that appear in every set. This intersecting set encodes secreted plasma glycoproteins that mediate coagulation, complement activation, and innate immune responses, and enrichment analysis highlighted blood coagulation, fibrin clot formation, platelet activation, and related immune pathways. The convergence of glycosylation information, ageassociated expression changes, and perturbation effects underscores a coherent molecular signature linking extracellular matrix stability, hemostasis, and inflammation, suggesting that coordinated regulation of these plasma proteins may be a pivotal feature of agerelated physiological alterations.