An integrated multi-omics approach identifies epigenetic alterations associated with Alzheimer's disease.
Acetylation
Alzheimer Disease
/ genetics
Amyloid beta-Peptides
/ genetics
Chromatin
/ genetics
Epigenome
/ genetics
Histone Acetyltransferases
/ genetics
Histone Code
/ genetics
Histones
/ genetics
Humans
Peptide Fragments
/ genetics
Protein Aggregation, Pathological
/ genetics
Proteome
/ genetics
Signal Transduction
/ genetics
Transcriptional Activation
/ genetics
Transcriptome
/ genetics
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
01
06
2019
accepted:
20
08
2020
pubmed:
30
9
2020
medline:
25
11
2020
entrez:
29
9
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32989324
doi: 10.1038/s41588-020-0696-0
pii: 10.1038/s41588-020-0696-0
pmc: PMC8098004
mid: NIHMS1622396
doi:
Substances chimiques
Amyloid beta-Peptides
0
Chromatin
0
Histones
0
Peptide Fragments
0
Proteome
0
amyloid beta-protein (1-42)
0
Histone Acetyltransferases
EC 2.3.1.48
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1024-1035Subventions
Organisme : NIA NIH HHS
ID : P30 AG010124
Pays : United States
Organisme : NIA NIH HHS
ID : U54 AG052427
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG000255
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA196539
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG031862
Pays : United States
Organisme : NIA NIH HHS
ID : U24 AG041689
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI118891
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS111997
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS097275
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG006827
Pays : United States
Commentaires et corrections
Type : ErratumIn
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