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The Use of Primary Human Fibroblasts for Monitoring Mitochondrial Phenotypes in the Field of Parkinson's Disease
Published on: October 3, 2012
Mitoepigenetic Alterations in Early-Onset Parkinson's Disease
Rana Abu Manneh1,2, Paraskevi P Chairta1, Maria A Loizidou2
1Neuroepidemiology Department, The Cyprus Institute of Neurology and Genetics, Nicosia 2371, Cyprus.
Abstract:
There is accumulating evidence that distinct mitochondrial DNA (mtDNA) methylation and hydroxymethylation patterns exist in Parkinson's disease (PD). However, most studies have been limited to the investigation of specific target regions, rather than the entire mtDNA, and have been further hindered by other methodological discrepancies and the lack of non-CpG context investigation. Here, we provide a comprehensive profile of methylation and hydroxymethylation levels across the mitochondrial genome, at global and single-base resolution, in CpG and non-CpG (CHG, CHH) contexts in blood samples from early-onset PD (EOPD) patients (n = 39) and age- and sex-matched controls (n = 63). Bisulfite (BS) and oxidative-bisulfite (oxBS) conversions in parallel workflows followed by next-generation sequencing (NGS) using Illumina's Novaseq 6000 sequencing system identified mitochondrial 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in all contexts. Global mtDNA methylation was significantly higher in EOPD patients vs. matched controls in the CpG context (p = 5.63 × 10-3) in the BS status, and in all contexts [CpG (p = 2.67 × 10-4), CHG (p = 0.015), CHH (p = 0.012)] in the oxBS status, i.e., "true methylation". At single-base resolution, the most statistically significant sites across the mitogenome, in the D-loop region, and CpG context, were primarily hypomethylated in EOPD patients compared to matched controls. Upon further validation, both global and base resolution mtDNA (hydroxy)methylation results could act as blood-based biomarkers for EOPD.
Insights
Mitochondrial DNA (mtDNA) methylation patterns differ in early-onset Parkinson's disease (EOPD). These epigenetic changes, including methylation and hydroxymethylation across the entire mtDNA, show potential as blood-based biomarkers for EOPD diagnosis.
Area of Science:
- Epigenetics
- Neuroscience
- Genomics
Background:
- Distinct mitochondrial DNA (mtDNA) methylation and hydroxymethylation patterns are increasingly linked to Parkinson's disease (PD).
- Previous studies focused on specific mtDNA regions, lacked non-CpG context analysis, and faced methodological limitations.
- A comprehensive analysis of the entire mitochondrial genome's epigenetic landscape in early-onset PD (EOPD) is needed.
Purpose of the Study:
- To comprehensively profile global and single-base resolution methylation and hydroxymethylation across the entire mitochondrial genome.
- To investigate these epigenetic modifications in both CpG and non-CpG contexts in blood samples from EOPD patients and controls.
- To evaluate the potential of mtDNA (hydroxy)methylation patterns as blood-based biomarkers for EOPD.
Main Methods:
- Blood samples from 39 EOPD patients and 63 age- and sex-matched controls were analyzed.
- Parallel workflows using bisulfite (BS) and oxidative-bisulfite (oxBS) conversions followed by next-generation sequencing (NGS) were employed.
- Mitochondrial 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) were identified in CpG, CHG, and CHH contexts.
Main Results:
- Global mtDNA methylation was significantly higher in EOPD patients compared to controls in both BS and oxBS statuses (true methylation).
- Analysis at single-base resolution revealed predominantly hypomethylated sites in the D-loop region and CpG context in EOPD patients.
- Significant differences in methylation and hydroxymethylation were observed across all contexts (CpG, CHG, CHH) in EOPD.
Conclusions:
- Comprehensive analysis reveals significant alterations in global and site-specific mtDNA (hydroxy)methylation in EOPD.
- The identified epigenetic patterns in CpG and non-CpG contexts offer novel insights into PD pathogenesis.
- Both global and base-resolution mtDNA (hydroxy)methylation profiles demonstrate potential as reliable blood-based biomarkers for early-onset Parkinson's disease.
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