A genome‐wide profiling of brain DNA hydroxymethylation in Alzheimer's disease

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  • Jinying Zhao
    Department of Epidemiology, College of Public Health and Health Professions University of Florida Gainesville FL USA
  • Yun Zhu
    Department of Epidemiology, College of Public Health and Health Professions University of Florida Gainesville FL USA
  • Jingyun Yang
    Rush Alzheimer's Disease Center Rush University Medical Center Chicago IL USA
  • Lin Li
    Department of Human Genetics Emory University School of Medicine Atlanta GA USA
  • Hao Wu
    Department of Biostatistics and Bioinformatics Emory University School of Public Health Atlanta GA USA
  • Philip L. De Jager
    Department of Neurology Brigham and Women's Hospital Boston MA USA
  • Peng Jin
    Department of Human Genetics Emory University School of Medicine Atlanta GA USA
  • David A. Bennett
    Rush Alzheimer's Disease Center Rush University Medical Center Chicago IL USA

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<jats:title>Abstract</jats:title><jats:sec><jats:title>Introduction</jats:title><jats:p>DNA methylation is a key epigenetic mechanism in brain aging and Alzheimer's disease (AD). The newly discovered 5‐hydroxymethylcytosine mediates DNA demethylation, is highly abundant in the brain, and is dynamically regulated by life experiences. However, little is known about its genome‐wide patterns and potential role in AD.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Using a genome‐wide capture followed by high‐throughput sequencing, we studied the genome‐wide distribution of 5‐hydroxymethylcytosine at specific genomic loci in human AD brain and identified differentially hydroxymethylated regions (DhMRs) associated with AD pathology.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We identified 517 DhMRs significantly associated with neuritic plaques and 60 DhMRs associated with neurofibrillary tangles. DNA hydroxymethylation in gene bodies was predominantly positively correlated with <jats:italic>cis</jats:italic>‐acting gene expression. Moreover, genes showing differential hydroxymethylation were significantly enriched in neurobiological processes and clustered in functional gene ontology categories.</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>Our results reveal a critical role of DNA hydroxymethylation in AD pathology and provide mechanistic insight into the molecular mechanisms underlying AD.</jats:p></jats:sec>

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