DNA methylation signature of human hippocampus in Alzheimer's disease is linked to neurogenesis.
Adult
Aged
Aged, 80 and over
Alzheimer Disease
/ genetics
Cadaver
Case-Control Studies
DNA Methylation
Epigenesis, Genetic
Female
Genes, Homeobox
Genome-Wide Association Study
/ methods
Hippocampus
/ chemistry
Humans
Male
Middle Aged
Neurogenesis
Oligonucleotide Array Sequence Analysis
Phosphorylation
Promoter Regions, Genetic
tau Proteins
/ metabolism
Adult neurogenesis
Alzheimer’s
DNA methylation
Epigenetics
Hippocampus
Homeobox
Neurodevelopment
Poised promoters
Journal
Clinical epigenetics
ISSN: 1868-7083
Titre abrégé: Clin Epigenetics
Pays: Germany
ID NLM: 101516977
Informations de publication
Date de publication:
19 06 2019
19 06 2019
Historique:
received:
14
02
2019
accepted:
25
04
2019
entrez:
21
6
2019
pubmed:
21
6
2019
medline:
27
5
2020
Statut:
epublish
Résumé
Drawing the epigenome landscape of Alzheimer's disease (AD) still remains a challenge. To characterize the epigenetic molecular basis of the human hippocampus in AD, we profiled genome-wide DNA methylation levels in hippocampal samples from a cohort of pure AD patients and controls by using the Illumina 450K methylation arrays. Up to 118 AD-related differentially methylated positions (DMPs) were identified in the AD hippocampus, and extended mapping of specific regions was obtained by bisulfite cloning sequencing. AD-related DMPs were significantly correlated with phosphorylated tau burden. Functional analysis highlighted that AD-related DMPs were enriched in poised promoters that were not generally maintained in committed neural progenitor cells, as shown by ChiP-qPCR experiments. Interestingly, AD-related DMPs preferentially involved neurodevelopmental and neurogenesis-related genes. Finally, InterPro ontology analysis revealed enrichment in homeobox-containing transcription factors in the set of AD-related DMPs. These results suggest that altered DNA methylation in the AD hippocampus occurs at specific regulatory regions crucial for neural differentiation supporting the notion that adult hippocampal neurogenesis may play a role in AD through epigenetic mechanisms.
Sections du résumé
BACKGROUND
Drawing the epigenome landscape of Alzheimer's disease (AD) still remains a challenge. To characterize the epigenetic molecular basis of the human hippocampus in AD, we profiled genome-wide DNA methylation levels in hippocampal samples from a cohort of pure AD patients and controls by using the Illumina 450K methylation arrays.
RESULTS
Up to 118 AD-related differentially methylated positions (DMPs) were identified in the AD hippocampus, and extended mapping of specific regions was obtained by bisulfite cloning sequencing. AD-related DMPs were significantly correlated with phosphorylated tau burden. Functional analysis highlighted that AD-related DMPs were enriched in poised promoters that were not generally maintained in committed neural progenitor cells, as shown by ChiP-qPCR experiments. Interestingly, AD-related DMPs preferentially involved neurodevelopmental and neurogenesis-related genes. Finally, InterPro ontology analysis revealed enrichment in homeobox-containing transcription factors in the set of AD-related DMPs.
CONCLUSIONS
These results suggest that altered DNA methylation in the AD hippocampus occurs at specific regulatory regions crucial for neural differentiation supporting the notion that adult hippocampal neurogenesis may play a role in AD through epigenetic mechanisms.
Identifiants
pubmed: 31217032
doi: 10.1186/s13148-019-0672-7
pii: 10.1186/s13148-019-0672-7
pmc: PMC6585076
doi:
Substances chimiques
MAPT protein, human
0
tau Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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