Epigenome-wide study uncovers tau pathology-driven changes of chromatin organization in the aging human brain
Sarah E Sullivan,
Belinda J Kaskow,
Robert V Smith,
Andreas R Pfenning,
Bradley E. Bernstein,
Julie A Schneider,
Tracy L Young-Pearse,
David A. Bennett,
Philip L. De Jager
Posted 28 Feb 2018
bioRxiv DOI: 10.1101/273789 (published DOI: 10.1038/s41593-018-0291-1)
Posted 28 Feb 2018
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.
- Downloaded 1,157 times
- Download rankings, all-time:
- Site-wide: 10,948 out of 103,919
- In neuroscience: 1,694 out of 18,385
- Year to date:
- Site-wide: 70,949 out of 103,919
- Since beginning of last month:
- Site-wide: 55,866 out of 103,919
Downloads over time
Distribution of downloads per paper, site-wide
- 18 Dec 2019: We're pleased to announce PanLingua, a new tool that enables you to search for machine-translated bioRxiv preprints using more than 100 different languages.
- 21 May 2019: PLOS Biology has published a community page about Rxivist.org and its design.
- 10 May 2019: The paper analyzing the Rxivist dataset has been published at eLife.
- 1 Mar 2019: We now have summary statistics about bioRxiv downloads and submissions.
- 8 Feb 2019: Data from Altmetric is now available on the Rxivist details page for every preprint. Look for the "donut" under the download metrics.
- 30 Jan 2019: preLights has featured the Rxivist preprint and written about our findings.
- 22 Jan 2019: Nature just published an article about Rxivist and our data.
- 13 Jan 2019: The Rxivist preprint is live!