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

Author

Listed:
  • 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
    Vilnius University)

  • Viviane Labrie

    (Van Andel Research Institute
    Centre for Addiction and Mental Health
    Michigan State University)

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.

Suggested Citation

  • Peipei Li & Lee Marshall & Gabriel Oh & Jennifer L. Jakubowski & Daniel Groot & Yu He & Ting Wang & Arturas Petronis & Viviane Labrie, 2019. "Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer’s disease pathology and cognitive symptoms," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10101-7
    DOI: 10.1038/s41467-019-10101-7
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    Cited by:

    1. Liam McAllan & Damir Baranasic & Sergio Villicaña & Scarlett Brown & Weihua Zhang & Benjamin Lehne & Marco Adamo & Andrew Jenkinson & Mohamed Elkalaawy & Borzoueh Mohammadi & Majid Hashemi & Nadia Fer, 2023. "Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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