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

ABSTRACT: The large majority of Parkinson’s disease (PD) cases are due to a complex interaction between aging, genetics, and environmental factors and epigenetic mechanisms are thought to act as critical mediators of the complex interactions between aging, genetics, the environment, and disease. Evidence for a role of epigenetic regulation in PD has been building, particularly for DNA modifications, over the past 10-15 years. 5-methylcytosine (5mC) is one of the most well-studied epigenetic marks. However, there is a growing recognition that 5-hydroxymethylcytosine (5hmC) plays an important role in gene regulation as it has tissue-, cell-, and age-specific patterns across the genome distinct from 5mC. 5hmC occurs at its highest levels in the brain and is now thought to be particularly important in the central nervous system, particularly in the response to neurotoxicants. While multiple studies to date have explored the role of DNA modifications in PD, most studies have relied on bisulfite (BS) conversion, which does not distinguish between 5mC and 5hmC. Only a handful of existing studies focus specifically on 5hmC; these initial studies support a role for 5hmC in regulation of expression of genes important for PD pathogenesis and indicate that additional studies are warranted. Here, to identify changes in 5hmC in PD, we profiled 5hmC and 5-methylcytosine (5mC) simultaneously in an enriched neuronal population from PD post-mortem parietal cortex. This study expands on our previously published epigenome-wide association study (EWAS) performed on DNA isolated from neuron-enriched nuclei from human postmortem parietal cortex from the Banner Sun Health Research Institute Brain Bank. Because we previously used BS conversion and the Illumina MethylationEPIC array, we were unable to differentiation between 5mC and 5hmC. Here, we utilized additional DNA isolated from the samples and performed oxidative BS (oxBS) conversion paired with the EPIC array to specifically measure 5mC and estimate 5hmC from paired BS-oxBS data. From this, we analyzed both 5hmC and 5mC as related measures using our recently proposed mixed effects model for reconciling base-pair resolution 5mC and 5hmC data.

ORGANISM(S): Homo sapiens

PROVIDER: GSE267937 | GEO | 2025/12/10

REPOSITORIES: GEO

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Project description:5-hydroxymethylcytosine (5hmC), converted from 5-methylcytosine (5mC) by Tet enzymes, has recently drawn attention as the ‘sixth base’ of DNA since it is considered to be an intermediate of the demethylation pathway. Nonetheless, it remains to be addressed how 5hmC is linked to the development of human imprinting disorders. In this regard, conventional bisulfite (BS) treatment is unable to differentiate 5hmC from 5mC. It is thus hypothesized that BS conversion-derived ‘hypermethylation’ at imprinting control regions (ICRs), which may cause human imprinting disorders, would in fact be attributable to excessively increased levels of 5hmC as well as 5mC. To test this hypothesis, we applied the newly developed oxidative BS (oxBS) treatment to detect 5hmC in blood samples from Kagami-Ogata syndrome (KOS14) patients caused by perturbed expression of clustered imprinted genes on 14q32.2 resulting from the hypermethylation of ICRs at this locus, IG-DMR and MEG3-DMR. oxBS with pyrosequencing and cloning-based sequencing revealed that there were few amounts of 5hmC at the hypermethylated IG-DMR in blood samples from KOS14 patients. oxBS with genome-wide methylation array analysis demonstrated that global levels of 5hmC were very low with similar distribution patterns in blood samples from KOS14 patients and normal controls. We also confirmed the presence of a large amount of 5hmC in the brain sample from a normal control. 5hmC is not a major component in abnormally hypermethylated ICRs or at a global level, at least in blood from KOS14 patients. As the brain sample contained a large amount of 5hmC, the neural tissues of KOS14 patients are promising candidates for analysis in elucidating the role of 5hmC in the neurodevelopmental context. We generated illumina 450k DNA methylation data for BS or oxBS converted samples of three KOS14 blood samples, one control pooled blood sample and one control brain sample with two technical replicates for each sample.

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

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