Mitochondrial Dysfunction Induces Epigenetic Dysregulation by H3K27 Hyperacetylation to Perturb Active Enhancers in Parkinson’s Disease Models

Abstract

Genetic mutations explain only 10-15% of cases of Parkinson's disease (PD), while an overriding environmental component has been implicated in the etiopathogenesis of PD. But regardless of where the underlying triggers for the onset of familial and sporadic PD fall on the gene-environment axis, mitochondrial dysfunction emerges as a common mediator of dopaminergic neuronal degeneration. Herein, we employ a multidisciplinary approach to convincingly demonstrate that neurotoxicant exposure-and genetic mutation-driven mitochondrial dysfunction share a common mechanism of epigenetic dysregulation. Under both scenarios, lysine 27 acetylation of likely variant H3.2 (H3.2K27ac) increased in dopaminergic neuronal models of PD, thereby opening that region to active enhancer activity via H3K27 hyperacetylation. These vulnerable epigenomic loci represent potential transcription factor motifs for PD pathogenesis. We further confirmed the mitochondrial dysfunction induced H3K27ac during neurodegeneration in ex vivo models of PD. Our results reveal an exciting axis of 'exposure/mutation-mitochondrial dysfunction-metabolism-H3K27ac-transcriptome' for PD pathogenesis. Collectively, the novel mechanistic insights presented here interlinks mitochondrial dysfunction to epigenetic transcriptional regulation in dopaminergic degeneration as well as offer potential new epigenetic intervention strategies for PD.

Epigenetic Vulnerability of Insulator CTCF Motifs at Parkinson’s Disease-Associated Genes in Response to Neurotoxicant Rotenone

“…DNA methylation and histone acetylation are epigenetic modifications implicated in rotenone-induced neurotoxicity ( Huang et al, 2019 ). DNA hypomethylation has been reported in response to pesticide exposure ( Hou et al, 2012 ), and we discovered that rotenone reduces DNA methylation at DNMT1-dependent regions in the human genome ( Freeman et al, 2020 ).…”

“…Histone acetylation patterns have been more extensively studied in rotenone-induced PD due to its high correlation with gene expression and enhancer activation (Wang et al, 2008). Most studies agree that rotenone-induced neurodegeneration is associated with pathological hyperacetylation as a result of impaired homeostatic activity of HATs and HDACs (Feng et al, 2015;Park et al, 2016;Harrison et al, 2018;Wang et al, 2018;Huang et al, 2019).…”