Epigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer’s human brains

Hans Ulrich Klein, Cristin McCabe, Elizabeta Gjoneska, Sarah E. Sullivan, Belinda J. Kaskow, Anna Tang, Robert V. Smith, Jishu Xu, Andreas R. Pfenning, Bradley E. Bernstein, Alexander Meissner, Julie A. Schneider, Sara Mostafavi, Li Huei Tsai, Tracy L. Young-Pearse, David A. Bennett, Philip L. De Jager

Research output: Contribution to journalArticlepeer-review

156 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)37-46
Number of pages10
JournalNature Neuroscience
Volume22
Issue number1
DOIs
Publication statusPublished - 1 Jan 2019
Externally publishedYes

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