TY - JOUR
T1 - Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer’s disease pathology and cognitive symptoms
AU - Li, Peipei
AU - Marshall, Lee
AU - Oh, Gabriel
AU - Jakubowski, Jennifer L.
AU - Groot, Daniel
AU - He, Yu
AU - Wang, Ting
AU - Petronis, Arturas
AU - Labrie, Viviane
N1 - Funding Information:
We thank Miki Susic for technical assistance. We thank Dr. Peter Laird, Dr. Hui Shen and Dr. Patrik Brundin for comments on the manuscript. We also thank the Van Andel Research Institute Flow Cytometry, Genomics and Bioinformatics Core and the CAMH Sequencing Facility. V.L. is supported by grants from the Alzheimer’s Society of Canada (16 15), the Scottish Rite Charitable Foundation of Canada (15110), the Brain and Behavior Research Foundation (23482), the Department of Defense (PD170089) and a Gibby & Friends vs. Parky Award. A.P. is supported in part by the Canadian Institutes of Health Research (MOP-199170, MOP-119451 and MOP-77689), the US National Institutes of Health (MH088413), the Krembil Foundation and Brain Canada. We thank the London Neurodegenerative Diseases Brain Bank, Brains for Dementia Research and Medical Research Council (MRC) for the brain tissue provided. ROSMAP study data were provided by the Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago. ROSMAP data collection was supported through funding by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, R01AG36042 U01AG32984, U01AG46152, the Illinois Department of Public Health, and the Translational Genomics Research Institute. This work is dedicated to the memory of Gabrielle Frenette Labrie (1928–2017).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85065975737&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-10101-7
DO - 10.1038/s41467-019-10101-7
M3 - Article
C2 - 31113950
AN - SCOPUS:85065975737
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2246
ER -