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Mitochondrial Stress-induced H4K12 Hyperacetylation Dysregulates Transcription in Parkinson's Disease

ABSTRACT: Mitochondrial Stress-induced H4K12 Hyperacetylation Dysregulates Transcription in Parkinson's Disease

PROVIDER: PRJNA748073 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15194154_1.fastq.gz	Fastqsanger.gz
	SRR15194154_2.fastq.gz	Fastqsanger.gz
	SRR15194155_1.fastq.gz	Fastqsanger.gz
	SRR15194155_2.fastq.gz	Fastqsanger.gz
	SRR15194156_1.fastq.gz	Fastqsanger.gz

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Mitochondrial Stress-induced H4K12 Hyperacetylation Dysregulates Transcription in Parkinson's Disease

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Mitochondrial stress-induced H4K12 hyperacetylation dysregulates transcription in Parkinson's disease.

Project description:Aberrant epigenetic modification has been implicated in the pathogenesis of Parkinson's disease (PD), which is characterized by the irreversible loss of dopaminergic (DAergic) neurons. However, the mechanistic landscape of histone acetylation (ac) in PD has yet to be fully explored. Herein, we mapped the proteomic acetylation profiling changes at core histones H4 and thus identified H4K12ac as a key epigenomic mark in dopaminergic neuronal cells as well as in MitoPark animal model of PD. Notably, the significantly elevated H4K12ac deposition in post-mortem PD brains highlights its clinical relevance to human PD. Increased histone acetyltransferase (HAT) activity and decreased histone deacetylase 2 (HDAC2) and HDAC4 were found in experimental PD cell models, suggesting the HAT/HDAC imbalance associated with mitochondrial stress. Following our delineation of the proteasome dysfunction that possibly contributes to H4K12ac deposition, we characterized the altered transcriptional profile and disease-associated pathways in the MitoPark mouse model of PD. Our study uncovers the axis of mitochondrial impairment-H4K12ac deposition-altered transcription/disease pathways as a neuroepigenetic mechanism underlying PD pathogenesis. These findings provide mechanistic information for the development of potential pharmacoepigenomic translational strategies for PD.

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

Project description:We aim to explore the predominant mitochondrial dysfunctions in PD, with a focus on how altering the histone code contributes to PD pathogenesis. 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. 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.

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