Epigenetic regulation of the lineage specificity of primary human dermal lymphatic and blood vascular endothelial cells
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ORIGINAL PAPER
Epigenetic regulation of the lineage specificity of primary human dermal lymphatic and blood vascular endothelial cells Carlotta Tacconi1 · Yuliang He1 · Luca Ducoli1 · Michael Detmar1 Received: 10 April 2020 / Accepted: 1 September 2020 © The Author(s) 2020
Abstract Lymphatic and blood vascular endothelial cells (ECs) share several molecular and developmental features. However, these two cell types possess distinct phenotypic signatures, reflecting their different biological functions. Despite significant advances in elucidating how the specification of lymphatic and blood vascular ECs is regulated at the transcriptional level during development, the key molecular mechanisms governing their lineage identity under physiological or pathological conditions remain poorly understood. To explore the epigenomic signatures in the maintenance of EC lineage specificity, we compared the transcriptomic landscapes, histone composition (H3K4me3 and H3K27me3) and DNA methylomes of cultured matched human primary dermal lymphatic and blood vascular ECs. Our findings reveal that blood vascular lineage genes manifest a more ‘repressed’ histone composition in lymphatic ECs, whereas DNA methylation at promoters is less linked to the differential transcriptomes of lymphatic versus blood vascular ECs. Meta-analyses identified two transcriptional regulators, BCL6 and MEF2C, which potentially govern endothelial lineage specificity. Notably, the blood vascular endothelial lineage markers CD34, ESAM and FLT1 and the lymphatic endothelial lineage markers PROX1, PDPN and FLT4 exhibited highly differential epigenetic profiles and responded in distinct manners to epigenetic drug treatments. The perturbation of histone and DNA methylation selectively promoted the expression of blood vascular endothelial markers in lymphatic endothelial cells, but not vice versa. Overall, our study reveals that the fine regulation of lymphatic and blood vascular endothelial transcriptomes is maintained via several epigenetic mechanisms, which are crucial to the maintenance of endothelial cell identity. Keywords Blood endothelial cells · Lymphatic endothelial cells · Cell identity · Epigenetics · DNA methylation · Histone modifications
Introduction The lymphatic and the blood vasculature exert complementary functions in humans. While the blood vasculature represents a closed circulatory system essential for the delivery Carlotta Tacconi and Yuliang He have equally contributed to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10456-020-09743-9) contains supplementary material, which is available to authorized users. * Michael Detmar [email protected] 1
Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Vladimir‑Prelog‑Weg 3, HCI H303, 8093 Zurich, Switzerland
of oxygen and nutrients, the lymphatic circulation is responsible for draining interstitial fluid from peripheral tissues, also serving as a conduit for immune cell traffi
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