期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-019-10101-7
关键词
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资金
- Alzheimer's Society of Canada [16 15]
- Scottish Rite Charitable Foundation of Canada [15110]
- Brain and Behavior Research Foundation [23482]
- Department of Defense [PD170089]
- Gibby & Friends vs. Parky Award
- Canadian Institutes of Health Research [MOP-199170, MOP-119451, MOP-77689]
- US National Institutes of Health [MH088413]
- Krembil Foundation
- NIA [P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, R01AG36042 U01AG32984, U01AG46152]
- Illinois Department of Public Health
- Translational Genomics Research Institute
- Brain Canada
Epigenetic control of enhancers alters neuronal functions and may be involved in Alzheimer's disease (AD). Here, we identify enhancers in neurons contributing to AD by comprehensive fine-mapping of DNA methylation at enhancers, genome-wide. We examine 1.2 million CpG and CpH sites in enhancers in prefrontal cortex neurons of individuals with no/mild, moderate, and severe AD pathology (n = 101). We identify 1224 differentially methylated enhancer regions; most of which are hypomethylated at CpH sites in AD neurons. CpH methylation losses occur in normal aging neurons, but are accelerated in AD. Integration of epigenetic and transcriptomic data demonstrates a pro-apoptotic reactivation of the cell cycle in post-mitotic AD neurons. Furthermore, AD neurons have a large cluster of significantly hypomethylated enhancers in the DSCAML1 gene that targets BACE1. Hypomethylation of these enhancers in AD is associated with an upregulation of BACE1 transcripts and an increase in amyloid plaques, neurofibrillary tangles, and cognitive decline.
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