The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

Abstract

Endothelial cells play an important role in maintenance of the vascular system and the repair after injury. Under proinflammatory conditions, endothelial cells can acquire a mesenchymal phenotype by a process named endothelial-to-mesenchymal transition (EndMT), which affects the functional properties of endothelial cells. Here, we investigated the epigenetic control of EndMT. We show that the histone demethylase JMJD2B is induced by EndMT-promoting, proinflammatory, and hypoxic conditions. Silencing of JMJD2B reduced TGF-β2-induced expression of mesenchymal genes, prevented the alterations in endothelial morphology and impaired endothelial barrier function. Endothelial-specific deletion of JMJD2B in vivo confirmed a reduction of EndMT after myocardial infarction. EndMT did not affect global H3K9me3 levels but induced a site-specific reduction of repressive H3K9me3 marks at promoters of mesenchymal genes, such as Calponin (CNN1), and genes involved in TGF-β signaling, such as AKT Serine/Threonine Kinase 3 (AKT3) and Sulfatase 1 (SULF1). Silencing of JMJD2B prevented the EndMT-induced reduction of H3K9me3 marks at these promotors and further repressed these EndMT-related genes. Our study reveals that endothelial identity and function is critically controlled by the histone demethylase JMJD2B, which is induced by EndMT-promoting, proinflammatory, and hypoxic conditions, and supports the acquirement of a mesenchymal phenotype.

Endothelial Reprogramming by Disturbed Flow Revealed by Single-Cell RNA and Chromatin Accessibility Study

“…Consistent with the accessibility changes, the corresponding gene expression levels were also increased in ECs exposed to d-flow in E8. These results confirm that d-flow induced EndMT as expected ( Glaser et al, 2020 ; Lai et al, 2018 ; Mahmoud et al, 2017 ; Moonen et al, 2015 ; Ten Dijke et al, 2012 ).…”

Endothelial reprogramming by disturbed flow revealed by single-cell RNA and chromatin accessibility study

“…Consistent with the accessibility changes, the corresponding gene expression levels were also increased in ECs exposed to d-flow in E8. These results confirm that d-flow indeed induced EndMT as expected (Glaser et al, 2020;Lai et al, 2018;Mahmoud et al, 2017;Moonen et al, 2015;Ten Dijke et al, 2012;Warboys et al, 2019).…”

TGF-β-Induced Endothelial to Mesenchymal Transition in Disease and Tissue Engineering

“…The critical function of JMJD2B in EndMT was verified in vivo; endothelial specific depletion of JMJD2B in mice resulted in substantial fewer EndMT positive cardiac ECs in the heart after experimentally induced myocardial infarction. However, the reduced EndMT only resulted in a modest rescue of cardiac function 2 weeks after infarction (Glaser et al, 2020).…”

“…Thus, the lack of Stk40 augments the positive function of miR-31 in EndMT (Katsura et al, 2016). Recently, Glaser et al (2020) demonstrated that TGF-β2 as well as a combination of IL-1β/TGF-β1 or hypoxia increased the expression of the histone demethylase Jumonji domain-containing protein 2B (JMJD2B) in HUVECs. Interestingly, both siRNA-mediated silencing and pharmacological inhibition of JMJD2B greatly reduced TGF-β2induced EndMT in HUVECs as demonstrated by a deceased SM22α expression, preserved CDH5 expression and reduced endothelial permeability.…”