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

Klein, H.-U., McCabe, C., Gjoneska, E., Sarah E. Sullivan, S. E., Kaskow, B. J., Tang, A., et al. (2019). Epigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer's human brains. Nature Neuroscience, 22(1), 37-46. doi:10.1038/s41593-018-0291-1.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-4DB9-7 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-4DBA-6
Genre: Journal Article

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 Creators:
Klein, Hans-Ulrich , Author
McCabe, Cristin , Author
Gjoneska, Elizabeta , Author
Sarah E. Sullivan, Sarah E. , Author
Kaskow, Belinda J. , Author
Tang, Anna , Author
Smith, Robert V. , Author
Xu, Jishu , Author
Pfenning, Andreas R. , Author
Bernstein, Bradley E. , Author
Meissner, Alexander1, 2, Author              
Schneider, Julie A. , Author
Mostafavi, Sara , Author
Tsai, Li-Huei , Author
Young-Pearse, Tracy L. , Author
Bennett, David A. , Author
De Jager, Philip L. , Author
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
2Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA, ou_persistent22              

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 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.

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Language(s): eng - English
 Dates: 2018-11-132018-12-172019-01-01
 Publication Status: Published in print
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 Identifiers: DOI: 10.1038/s41593-018-0291-1
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Title: Nature Neuroscience
  Other : Nat. Neurosci.
Source Genre: Journal
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Publ. Info: New York, NY : Nature America Inc.
Pages: 10 Volume / Issue: 22 (1) Sequence Number: - Start / End Page: 37 - 46 Identifier: ISSN: 1097-6256
CoNE: https://pure.mpg.de/cone/journals/resource/954925610931