Cited by 381Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchEpigenetics and DNA Methylation

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An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease

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Nativio, Raffaella, Lan, Yemin, Donahue, Greg, Sidoli, Simone, Berson, Amit, Srinivasan, Ananth R., Shcherbakova, Oksana, Amlie-Wolf, Alexandre, Nie, Ji, Cui, Xiaolong, He, Chuan, Wang, Li-San, Garcia, Benjamin A., Trojanowski, John Q., Bonini, Nancy M., Berger, Shelley L.·2020·Nature Genetics

DOI 10.1038/s41588-020-0696-0PMC PMC8098004

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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.

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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: Nativio, Raffaella
Lan, Yemin
Donahue, Greg
Sidoli, Simone
Berson, Amit
Shcherbakova, Oksana
Amlie-Wolf, Alexandre
Cui, Xiaolong
He, Chuan
Garcia, Benjamin A.
Trojanowski, John Q.
Bonini, Nancy M.
Berger, Shelley L.
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2020-09-28
Volume: 52
Issue: 10
Pages: 1024-1035
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/s41588-020-0696-0
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
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
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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An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer’s disease

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