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 isolated datasets, which fragments insight and limits the discovery of shared molecular features across biological contexts. By crossing geneset libraries drawn from the Common Fund Data Ecosystem, we can combine complementary information, increase robustness, and reveal conserved programs that span disparate experiments. In this study we intersected three resources - the GlyGen Glycosylated Proteins library, which provides sets of proteins modified by glycans and thus poised to mediate extracellular interactions; the GTEx Tissue-Specific Aging Signatures library, which contributes bloodderived genes upregulated in younger versus older adults and highlights agerelated circulating factors; and the LINCS L1000 CRISPR KO Perturbation Signatures library, which supplies genes downregulated after SEPHS2 knockout and links perturbation responses to functional pathways. Among all possible threeway combinations we selected the crossing with the highest simultaneous inclusion of genes from each set, yielding a robust intersect of nineteen proteins present in all three libraries. Functional profiling of this shared set emphasized roles in coagulation, lipid transport, complement activation, and extracellular signaling, consistent with the discussion that these secreted, glycosylated proteins coordinate vascular, inflammatory, and metabolic processes relevant to aging. The convergence of statistical significance, enrichment of vascular and metabolic pathways, and the biological relevance of the constituent gene sets underscores the value of multilibrary crossing for uncovering coherent molecular programs within Common Fund datasets.