Format

Send to

Choose Destination
Nat Neurosci. 2019 Jan;22(1):37-46. doi: 10.1038/s41593-018-0291-1. Epub 2018 Dec 17.

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

Author information

1
Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.
2
Broad Institute, Cambridge, MA, USA.
3
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
4
Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
5
Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA.
6
Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
7
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
8
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
9
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
10
Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada.
11
Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada.
12
Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA. pld2115@cumc.columbia.edu.
13
Broad Institute, Cambridge, MA, USA. pld2115@cumc.columbia.edu.

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.

PMID:
30559478
DOI:
10.1038/s41593-018-0291-1

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center