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Optimized Analysis of DNA Methylation and Gene Expression from Small, Anatomically-defined Areas of the Brain
13:11

Optimized Analysis of DNA Methylation and Gene Expression from Small, Anatomically-defined Areas of the Brain

Published on: July 12, 2012

Parallel profiling of DNA methylation and hydroxymethylation highlights neuropathology-associated epigenetic

Adam R Smith1, Rebecca G Smith1, Ehsan Pishva1,2

  • 1College of Medicine and Health, University of Exeter Medical School, Exeter University, RILD Building Level 4, Royal Devon and Exeter Hospital, Barrack Rd, Exeter, EX2 5DW, UK.

Clinical Epigenetics
|March 23, 2019
PubMed
Abstract

Insights

This study investigated DNA methylation and hydroxymethylation in Alzheimer's disease (AD) brains. We identified specific gene regions with altered epigenetic patterns, revealing new insights into AD's complex molecular underpinnings.

Area of Science:

  • Neuroscience
  • Epigenetics
  • Genomics

Background:

  • Alzheimer's disease (AD) is a progressive neurodegenerative disorder linked to epigenetic dysfunction.
  • Previous studies could not differentiate DNA methylation and hydroxymethylation in AD.
  • DNA hydroxymethylation's role in AD remains underexplored despite its enrichment in the brain.

Purpose of the Study:

  • To identify neuropathology-associated differential DNA methylation and hydroxymethylation in the entorhinal cortex of Alzheimer's disease patients.
  • To distinguish the roles of DNA methylation and hydroxymethylation in AD pathogenesis.
  • To provide a comprehensive epigenome-wide association study (EWAS) for both modifications in AD.

Main Methods:

  • Utilized oxidative bisulfite conversion combined with the Illumina Infinium Human Methylation 450K microarray.
  • Analyzed DNA methylation and hydroxymethylation patterns in the entorhinal cortex.
  • Validated findings in an independent cohort using oxidative-bisulfite pyrosequencing.

Main Results:

  • Identified one differentially methylated position in the WNT5B gene.
  • Discovered a differentially hydroxymethylated region in the FBXL16 gene.
  • Found differentially methylated regions in ANK1 and ARID5B genes, and alterations in unmodified cytosine in ALLC and JAG2.
  • Replicated ANK1 hypermethylation and hypohydroxymethylation in an independent cohort.

Conclusions:

  • This is the first EWAS of both DNA methylation and hydroxymethylation in the Alzheimer's disease entorhinal cortex.
  • Demonstrated that previously reported ANK1 hypermethylation in AD was an underestimate due to confounding hypohydroxymethylation.
  • Highlighted the importance of considering both DNA methylation and hydroxymethylation for a complete understanding of AD epigenetics.
Keywords:
Alzheimer’s disease (AD)Ankyrin 1 (ANK1)BrainDNA hydroxymethylation (5hmC)DNA methylation (5mC)Entorhinal cortex (EC)EpigeneticsEpigenome-wide association study (EWAS)Illumina Infinium Human Methylation 450K microarray (450K array)

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