The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

• Type of Material: Article
• Authors: Simone F. Glaser, Goethe University; Andreas W. Heumueller, Goethe University; Lukas Tombor, Goethe University; Patrick Hofmann, Goethe University; Marion Muhly-Reinholz, Goethe University; Ariane Fischer, Goethe University; Stefan Guenther, DZHK; Karoline E. Kokot, Universitätsklinikum Leipzig; Hitoshi Okada, Kindai University; David Hassel, DZHK; Sandeep Kumar, Emory University; Hanjoong Jo, Emory University; Reinier A. Boon, Goethe University; Wesley Abplanalp, Goethe University; David John, Goethe University; Jes-Niels Boeckel, Goethe University; Stefanie Dimmeler, Goethe University
• Language: English
• Date: 2020-02-25
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2020 National Academy of Sciences. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1913481117
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 117
• Issue: 8
• Start Page: 4180
• End Page: 4187
• Keywords: HEPARAN-SULFATE 6-O-ENDOSULFATASE; CELLS; CONTRIBUTES; EXPRESSION; TARGET; H3K9me3; SULF1; TRANSFORMATION; Multidisciplinary Sciences; Science & Technology; JMJD2B; epigenetics; BETA-CATENIN; EndMT; Science & Technology - Other Topics; PROMOTES; SNAIL; CARDIAC FIBROSIS
• Research Categories: Biology, Cell; Chemistry, Biochemistry

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.