An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer's disease
Author(s)
Type
Journal Article
Abstract
Protein aggregation is the hallmark of neurodegeneration, but the molecular mechanisms underlying late-onset Alzheimer's disease (AD) are unclear. Here we integrated transcriptomic, proteomic and epigenomic analyses of postmortem human brains to identify molecular pathways involved in AD. RNA sequencing analysis revealed upregulation of transcription- and chromatin-related genes, including the histone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomic screening singled out H3K27ac and H3K9ac as the main enrichments specific to AD. In turn, epigenomic profiling revealed gains in the histone H3 modifications H3K27ac and H3K9ac linked to transcription, chromatin and disease pathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly model of AD exacerbated amyloid-β42-driven neurodegeneration. Together, these findings suggest that AD involves a reconfiguration of the epigenome, wherein H3K27ac and H3K9ac affect disease pathways by dysregulating transcription- and chromatin-gene feedback loops. The identification of this process highlights potential epigenetic strategies for early-stage disease treatment.
Date Issued
2020-10-01
Date Acceptance
2020-08-20
Citation
Nature Genetics, 2020, 52 (10), pp.1024-1035
ISSN
1061-4036
Publisher
Nature Research
Start Page
1024
End Page
1035
Journal / Book Title
Nature Genetics
Volume
52
Issue
10
Copyright Statement
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/32989324
PII: 10.1038/s41588-020-0696-0
Subjects
Acetylation
Alzheimer Disease
Amyloid beta-Peptides
Chromatin
Epigenome
Histone Acetyltransferases
Histone Code
Histones
Humans
Peptide Fragments
Protein Aggregation, Pathological
Proteome
Signal Transduction
Transcriptional Activation
Transcriptome
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2020-09-28