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An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease
Open accessAbstract
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.
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“Combined analyses of ChIP-seq and RNA-seq data have linked histone acetylation marks, including H3K27ac and H3K9ac, to transcriptional dysregulation affecting synaptic and chromatin-related genes104.”
From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [104]
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“We further compared 832 DEGs with bulk RNA-seq datasets from various brain regions in individuals with AD (80–84), gene members in GO terms related to apoptosis/neurodegeneration, and AD risk genes from Alzgene database, revealing distinct sets of DEGs with overlaps ranging from 8 to 135 genes (Table S7, page 2, 3 and 4).”
From Modeling late-onset Alzheimer’s disease neuropathology via direct neuronal reprogramming (2024) · cites this paper as [83]
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Metadata
- Authors
- Nativio, R., Lan, Y., Donahue, G., Sidoli, S., Berson, A., Srinivasan, A. R., Shcherbakova, O., Amlie-Wolf, A., Nie, J., Cui, X., He, C., Wang, L.-S., Garcia, B. A., Trojanowski, J. Q., Bonini, N. M., & Berger, S. L.
- Affiliations
- University of Pennsylvania (US)
- Albert Einstein College of Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Bonini, Nancy M.
- Berger, Shelley L.
- ORCID
- Venue
- Nature Genetics
- Published
- 2020-09-28
- Volume
- 52
- Issue
- 10
- Pages
- 1024-1035
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC8098004
- OpenAlex
- W3089451699
- Cited by
- 380
- References
- 116
- Citations by year
- 2026: 61 · 2025: 79 · 2024: 70 · 2023: 60 · 2022: 58 · 2021: 47 · 2020: 5
- FWCI
- 25.57
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-10-08)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute on Aging (P01AG031862, P30AG010124, U54AG052427, U24AG041689, T32AG000255)
- National Human Genome Research Institute (R01HG006827)
- National Cancer Institute (P01CA196539)
- National Institute of Allergy and Infectious Diseases (R01AI118891)
- National Institute of Neurological Disorders and Stroke (R35NS097275, R01NS111997)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- Alzheimer's disease, epigenetic modifications, histone acetyltransferase, chromatin regulation, transcriptional dysregulation, amyloid-beta 42, neurodegeneration, Drosophila model, multi-omics integration, postmortem brain
- MeSH terms
- Epigenome, Acetylation, Alzheimer Disease, Chromatin, Histones, Humans, Peptide Fragments, Signal Transduction, Transcriptional Activation, Amyloid beta-Peptides, Proteome, Histone Code, Histone Acetyltransferases, Transcriptome, Protein Aggregation, Pathological
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