Epigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in the aging and Alzheimer human brain

Accumulation of tau and amyloid-β are two pathologic hallmarks of Alzheimer’s disease. We conducted an epigenome-wide association study using the histone 3 lysine 9 acetylation (H3K9ac) mark in 669 aged human prefrontal cortices; in contrast with amyloid-β, tau protein burden had a broad effect on the epigenome, affecting 5,990 of 26,384 H3K9ac domains. Tau-related alterations aggregated in large genomic segments reflecting spatial chromatin organization, and the magnitude of these effects correlated with the segment’s nuclear lamina association. Functional relevance of these chromatin changes was demonstrated by (1) consistent transcriptional changes in three independent datasets and (2) similar findings in two mouse models of Alzheimer’s disease. Finally, we found that tau overexpression in induced pluripotent stem cell-derived neurons altered chromatin structure and that these effects could be blocked by a small molecule predicted to reverse the tau effect. Thus, we report broad tau-driven chromatin rearrangements in the aging human brain that may be reversible with heat-shock protein 90 (Hsp90) inhibitors. Tau but not amyloid-beta pathology is associated with widespread alterations of histone 3 lysine 9 acetylation in the aged human cortex. Similar alterations of chromatin organization occur in iPSC-derived neurons after overexpression of tau.

• Publication year

  2018

• Venue

  Nature Neuroscience

• Publication date

  2018-11-24

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/s41593-018-0291-1PMID 30559478PMCID 6516529
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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