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Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells.

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.

SUBMITTER: Sabbagh MF

PROVIDER: S-EPMC6126923 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells.

Sabbagh Mark F MF Heng Jacob S JS Luo Chongyuan C Castanon Rosa G RG Nery Joseph R JR Rattner Amir A Goff Loyal A LA Ecker Joseph R JR Nathans Jeremy J

eLife 20180906

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 <i>cis</i>-regulatory elements reveals both shared and organ-specific EC regulatory networ ...[more]

PMID: 30188322

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Project description: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.

Project description:BackgroundHuman blood develops from self-renewing hematopoietic stem cells to terminal lineages and necessitates regulator and effector gene expression changes; each cell type specifically expresses a subset of genes to carry out a specific function. Gene expression changes coincide with histone modification, histone variant deposition, and recruitment of transcription-related enzymes to specific genetic loci. Transcriptional regulation has been mostly studied using in vitro systems while epigenetic changes occurring during in vivo development remain poorly understood.ResultsBy integrating previously published and novel global expression profiles from human CD34+/CD133+ hematopoietic stem and progenitor cells (HSPCs), in vivo differentiated human CD4+ T-cells and CD19+ B-cells, and in vitro differentiated CD36+ erythrocyte precursors, we identified hundreds of transcripts specifically expressed in each cell type. To relate concurrent epigenomic changes to expression, we examined genome-wide distributions of H3K4me1, H3K4me3, H3K27me1, H3K27me3, histone variant H2A.Z, ATP-dependent chromatin remodeler BRG1, and RNA Polymerase II in these cell types, as well as embryonic stem cells. These datasets revealed that numerous differentiation genes are primed for subsequent downstream expression by BRG1 and PolII binding in HSPCs, as well as the bivalent H3K4me3 and H3K27me3 modifications in the HSPCs prior to their expression in downstream, differentiated cell types; much HSPC bivalency is retained from embryonic stem cells. After differentiation, bivalency resolves to active chromatin configuration in the specific lineage, while it remains in parallel differentiated lineages. PolII and BRG1 are lost in closer lineages; bivalency resolves to silent monovalency in more distant lineages. Correlation of expression with epigenomic changes predicts tens of thousands of potential common and tissue-specific enhancers, which may contribute to expression patterns and differentiation pathways.ConclusionsSeveral crucial lineage factors are bivalently prepared for their eventual expression or repression. Bivalency is not only resolved during differentiation but is also established in a step-wise manner in differentiated cell types. We note a progressive, specific silencing of alternate lineage genes in certain cell types coinciding with H3K27me3 enrichment, though expression silencing is maintained in its absence. Globally, the expression of type-specific genes across many cell types correlates strongly with their epigenetic profiles. These epigenomic data appear useful for further understanding mechanisms of differentiation and function of human blood lineages.

Dataset Information

Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells.

Publications

Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells.

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