Abstract
BackgroundEndothelial cells (ECs) make up the innermost layer throughout the entire vasculature. Their phenotypes and physiological functions are initially regulated by developmental signals and extracellular stimuli. The underlying molecular mechanisms responsible for the diverse phenotypes of ECs from different organs are not well understood.ResultsTo characterize the transcriptomic and epigenomic landscape in the vascular system, we cataloged gene expression and active histone marks in nine types of human ECs (generating 148 genome-wide datasets) and carried out a comprehensive analysis with chromatin interaction data. We developed a robust procedure for comparative epigenome analysis that circumvents variations at the level of the individual and technical noise derived from sample preparation under various conditions. Through this approach, we identified 3765 EC-specific enhancers, some of which were associated with disease-associated genetic variations. We also identified various candidate marker genes for each EC type. We found that the nine EC types can be divided into two subgroups, corresponding to those with upper-body origins and lower-body origins, based on their epigenomic landscape. Epigenomic variations were highly correlated with gene expression patterns, but also provided unique information. Most of the deferentially expressed genes and enhancers were cooperatively enriched in more than one EC type, suggesting that the distinct combinations of multiple genes play key roles in the diverse phenotypes across EC types. Notably, many homeobox genes were differentially expressed across EC types, and their expression was correlated with the relative position of each organ in the body. This reflects the developmental origins of ECs and their roles in angiogenesis, vasculogenesis and wound healing.ConclusionsThis comprehensive analysis of epigenome characterization of EC types reveals diverse transcriptional regulation across human vascular systems. These datasets provide a valuable resource for understanding the vascular system and associated diseases.
Highlights
Endothelial cells (ECs) make up the innermost layer throughout the entire vasculature
Reference epigenome generation across EC types To establish an epigenetic catalog for different EC types, we generated a total of 491 genome-wide datasets, consisting of 424 histone modification ChIP-seq and 67 paired-end RNA sequencing (RNA-seq) datasets, encompassing a total of 22.3 billion sequenced reads
Among the structures lined by these nine EC types, a group of two aortic, six common carotid and three coronary arteries is known as the “systemic arteries” and harbors arterial blood with 100 mmHg of oxygen tension and blood pressure in a range from 140 to 60 mmHg
Summary
Endothelial cells (ECs) make up the innermost layer throughout the entire vasculature. Endothelial cells (ECs), which make up the innermost blood vessel lining of the body, express diverse phenotypes that affect their morphology, physiological function and gene expression patterns in response to the extracellular environment, including the oxygen concentration, blood pressure and physiological stress. The long-lasting results from coronary bypass graft surgery indicate that vessels transplanted to a new environment differ in their outcome based on their origin as an artery or vein [6, 7]. Based on these observations, the elucidation of the molecular mechanisms underlying EC-type variability is critically important for understanding the development of vascular and circulation systems
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