Genomic cell lineage analysis uncovers novel endothelial gene expression programs for metabolic and immune regulation

Endothelial cells (ECs) take on a variety of cellular phenotypes that depend on their niches, making it difficult to discern lineage‐wide traits. Therefore, we sought to identify novel aspects of EC biology by defining a core EC transcriptional signature shared amongst ECs. We accomplished this by condensing multiple sources of EC transcriptomic and genomic data sets using multivariate statistics and phylogenetic analyses. Our comparative multi‐tissue analyses confirmed expected gene expression patterns such as Flt1 , Pecam1 , Cdh5 , Tek , and Ptprb as core elements of ECs. We also observed strong statistical associations for a variety of genes without prominent roles in ECs, such as the oncostatin M receptor ( Osmr) , cysteine and tyrosine rich 1 ( Cyyr1 ) and an uncharacterized cDNA sequence ( BC028528 ) that were always positively associated with ECs compared to other cell types. This implied that associations with tightly regulated genes can be obscured by EC variability but may be important for fundamental EC biology. Strikingly, hallmark interferon alpha and gamma gene sets were associated with all EC subtypes and ECs showed highest enrichment in an interferon alpha activation gene signature (p<1e‐15). More broadly, glycolytic and mitochondrial metabolic gene sets were strongly down‐regulated in resting ECs while regulatory transcriptional and translational program gene sets were up‐regulated in these cells. Together, these findings support the existence of key metabolic and immune regulators that are necessary for constitutive EC function in all lineages that can be carefully scrutinized by gene modulation in experimental systems. Support or Funding Information NIH T32