Parkinson’s disease-associated shifts between DNA methylation and DNA hydroxymethylation in human brain

Abstract

Background: The majority of PD cases are due to a complex interaction between aging, genetics, and environmental factors; epigenetic mechanisms are thought to act as important mediators of these risk factors. While multiple studies to date have explored the role of DNA modifications in PD, few focus on 5-hydroxymethylcytosine (5hmC), which is thought to be particularly important in the brain and the response to environmental exposures. Objectives: The goal of this study was to identify paired changes in 5hmC and 5-methylcytosine (5mC) in PD in enriched neuronal nuclie isolated from PD post-mortem parietal cortex and age- and sex-matched controls. Methods: We performed oxidative bisulfite (BS) conversion and paired it with our previously published BS-based EWAS to identify cytosines with significant shifts between these two related epigenetic marks. Interaction differentially modified cytosines (iDMCs) were identified using our recently published mixed effect model for co-analyzing βmC and βhmC data. Results: We identified 1,030 iDMCs with paired changes in 5mC and 5hmC (FDR < 0.05) that map to 695 genes, including the PD risk gene, DNAJC6 (PARK19). Conclusions: These data potentially links epigenetic regulation of the PARK19 locus in the pathogenesis of idiopathic PD. In addition, iDMC-containing genes have known functions in synaptic formation and function, cell cycle and senescence, neuroinflammation, and epigenetic regulation. These data suggest that there are significant shifts between 5mC and 5hmC associated with PD in genes relevant to PD pathogenesis that are not captured by analyzing BS-based data alone or by analyzing each mark as a distinct dataset.