Jinying Zhao1, Yun Zhu2, Jingyun Yang3, Lin Li4, Hao Wu5, Philip L De Jager6, Peng Jin4, David A Bennett3. 1. Department of Epidemiology, College of Public Health and Health Professions, University of Florida, Gainesville, FL, USA. Electronic address: jzhao5@tulane.edu. 2. Department of Epidemiology, College of Public Health and Health Professions, University of Florida, Gainesville, FL, USA. 3. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA. 4. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA. 5. Department of Biostatistics and Bioinformatics, Emory University School of Public Health, Atlanta, GA, USA. 6. Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
Abstract
INTRODUCTION: 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. METHODS: 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. RESULTS: 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 cis-acting gene expression. Moreover, genes showing differential hydroxymethylation were significantly enriched in neurobiological processes and clustered in functional gene ontology categories. DISCUSSION: Our results reveal a critical role of DNA hydroxymethylation in AD pathology and provide mechanistic insight into the molecular mechanisms underlying AD.
INTRODUCTION: 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. METHODS: Using a genome-wide capture followed by high-throughput sequencing, we studied the genome-wide distribution of 5-hydroxymethylcytosine at specific genomic loci in humanAD brain and identified differentially hydroxymethylated regions (DhMRs) associated with AD pathology. RESULTS: 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 cis-acting gene expression. Moreover, genes showing differential hydroxymethylation were significantly enriched in neurobiological processes and clustered in functional gene ontology categories. DISCUSSION: Our results reveal a critical role of DNA hydroxymethylation in AD pathology and provide mechanistic insight into the molecular mechanisms underlying AD.
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