Abstract
Vascular endothelial cell (EC) function depends on appropriate organ-specific molecular and cellular specializations. To explore genomic mechanisms that control this specialization, we have analyzed and compared the transcriptome, accessible chromatin, and DNA methylome landscapes from mouse brain, liver, lung, and kidney ECs. Analysis of transcription factor (TF) gene expression and TF motifs at candidate cis-regulatory elements reveals both shared and organ-specific EC regulatory networks. In the embryo, only those ECs that are adjacent to or within the central nervous system (CNS) exhibit canonical Wnt signaling, which correlates precisely with blood-brain barrier (BBB) differentiation and Zic3 expression. In the early postnatal brain, single-cell RNA-seq of purified ECs reveals (1) close relationships between veins and mitotic cells and between arteries and tip cells, (2) a division of capillary ECs into vein-like and artery-like classes, and (3) new endothelial subtype markers, including new validated tip cell markers.
Highlights
In vertebrates, the vascular and immune systems constitute the only classes of cells that come into close proximity to most other cell types in the body
The data are available for public exploration as the Vascular Endothelial Cell Trans-omics Resource Database (VECTRDB) at https://markfsabbagh.shinyapps.io/ vectrdb/ and https://github.com/mfsabbagh/EC_Genomics
In comparing central nervous system (CNS) versus non-CNS endothelial cell (EC), the most prominent differences in transcription factor (TF) motifs and TF expression include CNS EC-specific utilization of TCF/LEF and ZIC3 motifs and CNS EC-specific expression of TCF/LEF factors and ZIC3, implying a prominent role for canonical Wnt signaling and ZIC3 DNA binding in CNS EC-specific gene expression
Summary
The vascular and immune systems constitute the only classes of cells that come into close proximity to most other cell types in the body. These systems share the property that a small number of basic cell types are further divided into functionally and molecularly distinct subtypes, some of which are specialized for the tissues in which they reside. The highly permeable sinusoidal vascular endothelium of the liver acts as a sieve in which ECs form a discontinuous lining to allow efficient diffusional exchange between serum and hepatocytes.
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