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

Peipei Li, Lee Marshall, Gabriel Oh, Jennifer L. Jakubowski, Daniel Groot, Yu He, Ting Wang, Arturas Petronis and Viviane Labrie ()
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Peipei Li: Van Andel Research Institute
Lee Marshall: Van Andel Research Institute
Gabriel Oh: Centre for Addiction and Mental Health
Jennifer L. Jakubowski: Van Andel Research Institute
Daniel Groot: Centre for Addiction and Mental Health
Yu He: Washington University in St. Louis
Ting Wang: Washington University in St. Louis
Arturas Petronis: Centre for Addiction and Mental Health
Viviane Labrie: Van Andel Research Institute

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10101-7

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DOI: 10.1038/s41467-019-10101-7

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