G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis

Author:

Rothammer Nicola1ORCID,Woo Marcel S.1ORCID,Bauer Simone1,Binkle-Ladisch Lars1ORCID,Di Liberto Giovanni2ORCID,Egervari Kristof2ORCID,Wagner Ingrid2ORCID,Haferkamp Undine3ORCID,Pless Ole3ORCID,Merkler Doron2ORCID,Engler Jan Broder1ORCID,Friese Manuel A.1ORCID

Affiliation:

1. Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, 20251 Hamburg, Germany.

2. Department of Pathology and Immunology, Division of Clinical Pathology, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.

3. Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, Germany.

Abstract

Neuroinflammation leads to neuronal stress responses that contribute to neuronal dysfunction and loss. However, treatments that stabilize neurons and prevent their destruction are still lacking. Here, we identify the histone methyltransferase G9a as a druggable epigenetic regulator of neuronal vulnerability to inflammation. In murine experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS), we found that the G9a-catalyzed repressive epigenetic mark H3K9me2 was robustly induced by neuroinflammation. G9a activity repressed anti-ferroptotic genes, diminished intracellular glutathione levels, and triggered the iron-dependent programmed cell death pathway ferroptosis. Conversely, pharmacological treatment of EAE mice with a G9a inhibitor restored anti-ferroptotic gene expression, reduced inflammation-induced neuronal loss, and improved clinical outcome. Similarly, neuronal anti-ferroptotic gene expression was reduced in MS brain tissue and was boosted by G9a inhibition in human neuronal cultures. This study identifies G9a as a critical transcriptional enhancer of neuronal ferroptosis and potential therapeutic target to counteract inflammation-induced neurodegeneration.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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