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dc.contributor.authorKlein, Hans-Ulrich
dc.contributor.authorMcCabe, Cristin
dc.contributor.authorGjoneska, Elizabeta
dc.contributor.authorSullivan, Sarah E
dc.contributor.authorKaskow, Belinda J
dc.contributor.authorTang, Anna
dc.contributor.authorSmith, Robert V
dc.contributor.authorXu, Jishu
dc.contributor.authorPfenning, Andreas R
dc.contributor.authorBernstein, Bradley E
dc.contributor.authorMeissner, Alexander
dc.contributor.authorSchneider, Julie A
dc.contributor.authorMostafavi, Sara
dc.contributor.authorTsai, Li-Huei
dc.contributor.authorYoung-Pearse, Tracy L
dc.contributor.authorBennett, David A
dc.contributor.authorDe Jager, Philip L
dc.date.accessioned2021-12-06T19:49:21Z
dc.date.available2021-12-06T19:49:21Z
dc.date.issued2019
dc.identifier.urihttps://hdl.handle.net/1721.1/138336
dc.description.abstract© 2018, The Author(s), under exclusive licence to Springer Nature America, Inc. 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.en_US
dc.language.isoen
dc.publisherSpringer Natureen_US
dc.relation.isversionof10.1038/S41593-018-0291-1en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourcePMCen_US
dc.titleEpigenome-wide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer’s human brainsen_US
dc.typeArticleen_US
dc.identifier.citationKlein, Hans-Ulrich, McCabe, Cristin, Gjoneska, Elizabeta, Sullivan, Sarah E, Kaskow, Belinda J 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).
dc.contributor.departmentPicower Institute for Learning and Memory
dc.relation.journalNature Neuroscienceen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2021-12-06T19:42:58Z
dspace.orderedauthorsKlein, H-U; McCabe, C; Gjoneska, E; Sullivan, SE; Kaskow, BJ; Tang, A; Smith, RV; Xu, J; Pfenning, AR; Bernstein, BE; Meissner, A; Schneider, JA; Mostafavi, S; Tsai, L-H; Young-Pearse, TL; Bennett, DA; De Jager, PLen_US
dspace.date.submission2021-12-06T19:43:00Z
mit.journal.volume22en_US
mit.journal.issue1en_US
mit.licensePUBLISHER_POLICY
mit.metadata.statusAuthority Work and Publication Information Neededen_US


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