HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia
- Taranjit Singh Rai1,2,3,
- John J. Cole1,2,5,
- David M. Nelson1,2,5,
- Dina Dikovskaya1,2,
- William J. Faller1,
- Maria Grazia Vizioli1,2,
- Rachael N. Hewitt1,2,
- Orchi Anannya1,
- Tony McBryan1,2,
- Indrani Manoharan1,2,
- John van Tuyn1,2,
- Nicholas Morrice1,
- Nikolay A. Pchelintsev1,2,
- Andre Ivanov1,2,4,
- Claire Brock1,2,
- Mark E. Drotar1,2,
- Colin Nixon1,
- William Clark1,
- Owen J. Sansom1,
- Kurt I. Anderson1,
- Ayala King1,
- Karen Blyth1 and
- Peter D. Adams1,2
- 1Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom;
- 2Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom;
- 3Institute of Biomedical and Environmental Health Research, University of West of Scotland, Paisley PA1 2BE, United Kingdom
- Corresponding authors: p.adams{at}beatson.gla.ac.uk, taranjitsingh.rai{at}uws.ac.uk
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↵5 These authors contributed equally to this work.
Abstract
Cellular senescence is a stable proliferation arrest that suppresses tumorigenesis. Cellular senescence and associated tumor suppression depend on control of chromatin. Histone chaperone HIRA deposits variant histone H3.3 and histone H4 into chromatin in a DNA replication-independent manner. Appropriately for a DNA replication-independent chaperone, HIRA is involved in control of chromatin in nonproliferating senescent cells, although its role is poorly defined. Here, we show that nonproliferating senescent cells express and incorporate histone H3.3 and other canonical core histones into a dynamic chromatin landscape. Expression of canonical histones is linked to alternative mRNA splicing to eliminate signals that confer mRNA instability in nonproliferating cells. Deposition of newly synthesized histones H3.3 and H4 into chromatin of senescent cells depends on HIRA. HIRA and newly deposited H3.3 colocalize at promoters of expressed genes, partially redistributing between proliferating and senescent cells to parallel changes in expression. In senescent cells, but not proliferating cells, promoters of active genes are exceptionally enriched in H4K16ac, and HIRA is required for retention of H4K16ac. HIRA is also required for retention of H4K16ac in vivo and suppression of oncogene-induced neoplasia. These results show that HIRA controls a specialized, dynamic H4K16ac-decorated chromatin landscape in senescent cells and enforces tumor suppression.
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Footnotes
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Supplemental material is available for this article.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.247528.114.
- Received June 15, 2014.
- Accepted November 4, 2014.
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