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

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G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis. / Rothammer, Nicola; Woo, Marcel S; Bauer, Simone; Binkle-Ladisch, Lars; Di Liberto, Giovanni; Egervari, Kristof; Wagner, Ingrid; Haferkamp, Undine; Pless, Ole; Merkler, Doron; Engler, Jan Broder; Friese, Manuel A.

In: SCI ADV, Vol. 8, No. 31, eabm5500, 05.08.2022.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Rothammer, N, Woo, MS, Bauer, S, Binkle-Ladisch, L, Di Liberto, G, Egervari, K, Wagner, I, Haferkamp, U, Pless, O, Merkler, D, Engler, JB & Friese, MA 2022, 'G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis', SCI ADV, vol. 8, no. 31, eabm5500. https://doi.org/10.1126/sciadv.abm5500

APA

Rothammer, N., Woo, M. S., Bauer, S., Binkle-Ladisch, L., Di Liberto, G., Egervari, K., Wagner, I., Haferkamp, U., Pless, O., Merkler, D., Engler, J. B., & Friese, M. A. (2022). G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis. SCI ADV, 8(31), [eabm5500]. https://doi.org/10.1126/sciadv.abm5500

Vancouver

Rothammer N, Woo MS, Bauer S, Binkle-Ladisch L, Di Liberto G, Egervari K et al. G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis. SCI ADV. 2022 Aug 5;8(31). eabm5500. https://doi.org/10.1126/sciadv.abm5500

Bibtex

@article{7022b2f6b8bf4200bbf7b2741bf4f518,
title = "G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis",
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.",
keywords = "Animals, Encephalomyelitis, Autoimmune, Experimental/genetics, Ferroptosis/genetics, Gene Expression Regulation, Histone-Lysine N-Methyltransferase/metabolism, Humans, Inflammation/genetics, Mice, Multiple Sclerosis, Neurons/metabolism",
author = "Nicola Rothammer and Woo, {Marcel S} and Simone Bauer and Lars Binkle-Ladisch and {Di Liberto}, Giovanni and Kristof Egervari and Ingrid Wagner and Undine Haferkamp and Ole Pless and Doron Merkler and Engler, {Jan Broder} and Friese, {Manuel A}",
year = "2022",
month = aug,
day = "5",
doi = "10.1126/sciadv.abm5500",
language = "English",
volume = "8",
journal = "SCI ADV",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "31",

}

RIS

TY - JOUR

T1 - G9a dictates neuronal vulnerability to inflammatory stress via transcriptional control of ferroptosis

AU - Rothammer, Nicola

AU - Woo, Marcel S

AU - Bauer, Simone

AU - Binkle-Ladisch, Lars

AU - Di Liberto, Giovanni

AU - Egervari, Kristof

AU - Wagner, Ingrid

AU - Haferkamp, Undine

AU - Pless, Ole

AU - Merkler, Doron

AU - Engler, Jan Broder

AU - Friese, Manuel A

PY - 2022/8/5

Y1 - 2022/8/5

N2 - 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.

AB - 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.

KW - Animals

KW - Encephalomyelitis, Autoimmune, Experimental/genetics

KW - Ferroptosis/genetics

KW - Gene Expression Regulation

KW - Histone-Lysine N-Methyltransferase/metabolism

KW - Humans

KW - Inflammation/genetics

KW - Mice

KW - Multiple Sclerosis

KW - Neurons/metabolism

U2 - 10.1126/sciadv.abm5500

DO - 10.1126/sciadv.abm5500

M3 - SCORING: Journal article

C2 - 35930635

VL - 8

JO - SCI ADV

JF - SCI ADV

SN - 2375-2548

IS - 31

M1 - eabm5500

ER -