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.

Loss of renal tubular G9a benefits acute kidney injury by lowering focal lipid accumulation via CES1

“…Moreover, G9a has recently been found to be a critical enhancer of neuronal ferroptosis. G9a activity represses anti‐ferroptotic genes, diminishes intracellular glutathione levels, and triggers an iron‐dependent programmed cell death pathway in an autoimmune encephalomyelitis mouse model (Rothammer et al , 2022). In the present study, no ferroptosis‐related pathway was enriched by knockout of G9a under I/R‐injury conditions using RNA‐sequence analysis.…”

MicroRNA-92a–CPEB3 axis protects neurons against inflammatory neurodegeneration

“…Primary cortical mouse neurons were prepared as described previously ( 9 ). Pregnant C57BL/6J or Cpeb3 fl/fl ;Snap25-Cre mice were euthanized on gestational day E15.5 to E16.5, and cortices of prenatal mice were isolated and trypsinized in 0.05% EDTA solution (Gibco, catalog no.…”

“…Primary cortical neurons were stimulated with bicuculline (25 μM) ( 34 ); the proinflammatory cytokines TNF-α, IFN-γ, or IL-1β (100 ng ml −1 ) ( 53 ); or glutamate bath (1, 5, 10, and 20 μM) for 24 hours ( 9 , 34 ) to simulate chronic cell stress. Subsequently, neurons were washed twice in ice-cold sterile PBS without Ca/Mg [Dulbecco’s PBS (DPBS)] (PAN Biotech, catalog no.…”

“…RealTime-Glo MT cell viability assay (Promega, catalog no. G9711) was performed as described previously ( 9 ). Briefly, RealTime-Glo reagents were mixed and added to neuronal cultures in 96-well microplate format (μclear, Greiner, catalog no.…”

“…Recently, single-cell transcriptomic analysis of MS brains ( 7 ) and neuron-specific transcriptional profiling in experimental autoimmune encephalomyelitis (EAE) ( 8 ), a widely used animal model of MS, revealed pathways that contribute to MS pathology and are deregulated on a transcriptional level in neurons. As we have recently demonstrated for the presynaptic protein bassoon ( 8 ) and the epigenetic regulator G9a ( 9 ), neuron-specific transcriptional profiling in EAE led to the identification of factors that modulate neurodegeneration and can be therapeutically targeted. Both studies revealed substantial transcriptional dysregulation during inflammation, which in part appears to be driven by epigenetic changes.…”