The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition

Simone F Glaser, Andreas W Heumüller, Lukas Tombor, Patrick Hofmann, Marion Muhly-Reinholz, Ariane Fischer, Stefan Günther, Karoline E Kokot, David Hassel, Sandeep Kumar, Hanjoong Jo, Reinier A Boon, Wesley Abplanalp, David John, Jes-Niels Boeckel, Stefanie Dimmeler

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)4180-4187
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number8
Early online date7 Feb 2020
DOIs
Publication statusPublished - 25 Feb 2020

Cite this

Glaser, S. F., Heumüller, A. W., Tombor, L., Hofmann, P., Muhly-Reinholz, M., Fischer, A., ... Dimmeler, S. (2020). The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition. Proceedings of the National Academy of Sciences of the United States of America, 117(8), 4180-4187. https://doi.org/10.1073/pnas.1913481117