The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

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 propertie...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2020-02, Vol.117 (8), p.4180-4187
Main Authors: Glaser, Simone F., Heumüller, Andreas W., Tombor, Lukas, Hofmann, Patrick, Muhly-Reinholz, Marion, Fischer, Ariane, Gunther, Stefan, Kokot, Karoline E., Hassel, David, Kumar, Sandeep, Jo, Hanjoong, Boon, Reinier A., Abplanalp, Wesley, John, David, Boeckel, Jes-Niels, Dimmeler, Stefanie
Format: Article
Language:English
Subjects:
AKT protein
Biological Sciences
Calponin
Clonal deletion
Endothelial cells
Epigenetics
Gene expression
Genes
Histones
Hypoxia
Inflammation
Kinases
Mesenchyme
Morphology
Myocardial infarction
Phenotypes
Protein-serine/threonine kinase
Reduction
Vascular system
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1913481117