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Comprehensive epigenome characterization reveals diverse transcriptional regulation across human vascular endothelial cells.

ABSTRACT: BACKGROUND:Endothelial 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. RESULTS:To 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. CONCLUSIONS:This 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.

SUBMITTER: Nakato R

PROVIDER: S-EPMC6921469 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Comprehensive epigenome characterization reveals diverse transcriptional regulation across human vascular endothelial cells.

Nakato Ryuichiro R Wada Youichiro Y Nakaki Ryo R Nagae Genta G Katou Yuki Y Tsutsumi Shuichi S Nakajima Natsu N Fukuhara Hiroshi H Iguchi Atsushi A Kohro Takahide T Kanki Yasuharu Y Saito Yutaka Y Kobayashi Mika M Izumi-Taguchi Akashi A Osato Naoki N Osato Naoki N Tatsuno Kenji K Kamio Asuka A Hayashi-Takanaka Yoko Y Wada Hiromi H Ohta Shinzo S Aikawa Masanori M Nakajima Hiroyuki H Nakamura Masaki M McGee Rebecca C RC Heppner Kyle W KW Kawakatsu Tatsuo T Genno Michiru M Yanase Hiroshi H Kume Haruki H Senbonmatsu Takaaki T Homma Yukio Y Nishimura Shigeyuki S Mitsuyama Toutai T Aburatani Hiroyuki H Kimura Hiroshi H Shirahige Katsuhiko K

Epigenetics & chromatin 20191219 1

<h4>Background</h4>Endothelial 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.<h4>Results</h4>To characterize the transcriptomic and epigenomic landscape in the vascular system, we cataloged gene expression and active histo ...[more]

PMID: 31856914

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Project description:BackgroundInterleukin 6 (IL6) is a multifunctional cytokine produced by various cells, including vascular endothelial cells. IL6 has both pro- and non-/anti-inflammatory functions, and the response to IL6 is dependent on whether it acts via the membrane-bound IL6 receptor α (IL6Rα) (classic signaling) or the soluble form of the receptor (transsignaling). As human endothelial cells produce IL6 and at the same time express IL6Rα, we hypothesized that IL6 may have autocrine functions.MethodsKnockdown of IL6 in cultured human endothelial cells was performed using siRNA. Knockdown efficiency was evaluated using ELISA. RNA sequencing was employed to characterize the transcriptional consequence of IL6 knockdown, and Ingenuity Pathway Analysis was used to further explore the functional roles of IL6.ResultsKnockdown of IL6 in cultured endothelial cells resulted in a 84-92% reduction in the release of IL6. Knockdown of IL6 resulted in dramatic changes in transcriptional pattern; knockdown of IL6 in the absence of soluble IL6Rα (sIL6Rα) led to differential regulation of 1915 genes, and knockdown of IL6 in the presence of sIL6Rα led to differential regulation of 1967 genes (fold change 1.5, false discovery rate < 0.05). Pathway analysis revealed that the autocrine functions of IL6 in human endothelial cells are mainly related to basal cellular functions such as regulation of cell cycle, signaling, and cellular movement. Furthermore, we found that knockdown of IL6 activates functions related to adhesion, binding, and interaction of endothelial cells, which seem to be mediated mainly via STAT3.ConclusionIn this study, a large number of novel genes that are under autocrine regulation by IL6 in human endothelial cells were identified. Overall, our data indicate that IL6 acts in an autocrine manner to regulate basal cellular functions, such as cell cycle regulation, signaling, and cellular movement, and suggests that the autocrine functions of IL6 in human endothelial cells are mediated via IL6 classic signaling.

Dataset Information

Comprehensive epigenome characterization reveals diverse transcriptional regulation across human vascular endothelial cells.

Publications

Comprehensive epigenome characterization reveals diverse transcriptional regulation across human vascular endothelial cells.

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