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Nat Commun. 2019 May 21;10(1):2246. doi: 10.1038/s41467-019-10101-7.

Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer's disease pathology and cognitive symptoms.

Author information

1
Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, 49503, USA.
2
Centre for Addiction and Mental Health, Toronto, M5T 1R8, ON, Canada.
3
Department of Genetics, Washington University in St. Louis, St. Louis, MO, 63130, USA.
4
Institute of Biotechnology, Life Sciences Center, Vilnius University, LT-10257, Vilnius, Lithuania.
5
Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, 49503, USA. viviane.labrie@vai.org.
6
Centre for Addiction and Mental Health, Toronto, M5T 1R8, ON, Canada. viviane.labrie@vai.org.
7
Division of Psychiatry and Behavioral Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA. viviane.labrie@vai.org.

Abstract

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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