期刊
ALZHEIMERS & DEMENTIA
卷 13, 期 6, 页码 674-688出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jalz.2016.10.004
关键词
Alzheimer's disease; Postmortem brain; DNA hydroxymethylation; Genome-wide association; Epigenetics
资金
- National Institutes of Health [R01DK091369, R01MH097018, P30AG10161, RF1AG15819, R01AG17917, R01AG16042, U01AG46152, R01AG36836]
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. (C) 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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