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Differential 5-methylcytosine and 5-hydroxymethylcytosine in Parkinson’s and Alzheimer’s Disease.

ABSTRACT: Differential 5-methylcytosine and 5-hydroxymethylcytosine in Parkinson’s and Alzheimer’s Disease.

PROVIDER: PRJNA576484 | ENA |

REPOSITORIES: ENA

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Differential 5-methylcytosine and 5-hydroxymethylcytosine in Parkinson’s and Alzheimer’s Disease.

Project description:Background: 5-methylcytosine (5-mC) and its oxidized form, 5-hydroxymethylcytosine (5-hmC), are distinct epigenetic marks that help regulate gene expression in the mammalian brain. Existing studies have identified associations between 5-mC and neurodegenerative disease, but little work has examined the potential role of 5-hmC in Parkinson’s disease (PD) or Alzheimer’s disease (AD). Here, we utilized PD postmortem brain tissue and a public dataset from postmortem AD brains to analyze the effect of neurodegenerative disease on paired 5-mC and 5-hmC levels. Results: In PD samples, we measured genome-wide 5-mC and 5-hmC from control (n=3) and PD (n=6) brains using the Illumina EPIC array combined with bisulfite and oxidative bisulfite treatments (BS/oxBS-EPIC). In publicly sourced data, genome-wide 5-mC and 5-hmC were measured from control (n=25) and AD (n=62) human entorhinal cortex tissue using the Illumina 450K array combined with bisulfite and oxidative bisulfite treatment (BS/oxBS-450K). Paired 5-mC and 5-hmC beta values were generated using a custom pipeline of bioinformatics tools, and we modeled the effect of disease on paired 5-mC and 5-hmC data using a mixed effects beta regression model with a random effect for ID and an interaction term between disease category and DNA modification category (“5-mC” or “5-hmC”). We identified a number of CpG probes (AD: n=699, PD: total n = 80) that showed a significant interaction between disease status and DNA modification category (p-value < 2.4x10-7). Conclusions: While our PD data requires additional validation, our analyses suggest that there are widespread shifts in the balance between 5-mC and 5-hmC in Parkinson’s and Alzheimer’s disease.

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Project description:DNA 5-hydroxymethylcytosine (5hmC), also known as the sixth DNA base of the genome, plays an important role in neurogenerative disorders. However, little is known about its genome-wide distribution and its association with Alzheimer’s disease neuropathology. Here, we report a genome-wide profiling of 5hmC in 1,050 autopsied brains (dorsolateral prefrontal cortex) of older adults in the Religious Orders Study/Memory and Aging Project (ROSMAP) cohorts. This resource will facilitate future research of DNA methylation and demethylation in Alzheimer’s disease and other neurological disorders.

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