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Epigenome-wide study uncovers tau pathology-driven changes of chromatin organization in the aging human brain

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
doi: https://doi.org/10.1101/273789
Hans-Ulrich Klein
1Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, New York, USA
2Broad Institute, Cambridge, Massachusetts, USA
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Cristin McCabe
2Broad Institute, Cambridge, Massachusetts, USA
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Elizabeta Gjoneska
2Broad Institute, Cambridge, Massachusetts, USA
3Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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Sarah E. Sullivan
4Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Belinda J. Kaskow
4Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Anna Tang
2Broad Institute, Cambridge, Massachusetts, USA
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Robert V. Smith
4Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Jishu Xu
2Broad Institute, Cambridge, Massachusetts, USA
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Andreas R. Pfenning
5Computational Biology Department, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA
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Bradley E. Bernstein
6Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
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Alexander Meissner
7Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA
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Julie A. Schneider
8Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, USA
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Sara Mostafavi
9Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
10Department of Statistics, University of British Columbia, Vancouver, British Columbia, Canada
11Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada
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Li-Huei Tsai
2Broad Institute, Cambridge, Massachusetts, USA
3Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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Tracy L. Young-Pearse
2Broad Institute, Cambridge, Massachusetts, USA
4Department of Neurology, Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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David A. Bennett
8Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois, USA
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Philip L. De Jager
1Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, New York, USA
2Broad Institute, Cambridge, Massachusetts, USA
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Summary

Accumulation of tau and amyloid-β are two pathologic hallmarks of Alzheimer’s disease (AD). Here, we conducted an epigenome-wide association study using the H3K9 acetylation (H3K9Ac) mark in 669 aged human prefrontal cortices: in contrast to amyloid-β, tau protein burden had a broad effect on the epigenome, affecting 5,590 out 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. We confirmed the functional relevance of these chromatin changes by demonstrating (1) consistent transcriptional changes in three independent datasets and (2) similar findings in two AD mouse models. Finally, we found that tau overexpression in iPSC-derived neurons disrupted chromatin organization and that these effects could be blocked by a small molecule predicted to reverse the tau effect. Thus, we report large-scale tau-driven chromatin rearrangements in the aging human brain that may be reversible with HSP90 inhibitors.

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Posted February 28, 2018.
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Epigenome-wide study uncovers tau pathology-driven changes of chromatin organization in the aging human brain
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
bioRxiv 273789; doi: https://doi.org/10.1101/273789
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Epigenome-wide study uncovers tau pathology-driven changes of chromatin organization in the aging human brain
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
bioRxiv 273789; doi: https://doi.org/10.1101/273789

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