HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia

Rai, T. S. et al. (2014) HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia. Genes and Development, 28(24), pp. 2712-2725. (doi:10.1101/gad.247528.114)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ivanov, Dr Andrejs and Cole, Mr John and Blyth, Dr Karen and Rai, Dr Taranjit and Vizioli, Dr Maria Grazia and Pchelintsev, Dr Nikolay and Anderson, Professor Kurt and King, Dr Ayala and Hewitt, Miss Rachael and Nixon, Mr Colin and Nelson, Mr David and Manoharan, Miss Indrani and Reid, Mrs Claire and Clark, Mr William and Drotar, Mr Mark and Adams, Professor Peter and Faller, Dr William and Dikovskaya, Dr Dina and McBryan, Dr Anthony and Sansom, Professor Owen and Morrice, Dr Nicholas
Authors: Rai, T. S., Cole, J. J., Nelson, D. M., Dikovskaya, D., Faller, W. J., Vizioli, M. G., Hewitt, R. N., Anannya, O., McBryan, A., Manoharan, I., van Tuyn, J., Morrice, N., Pchelintsev, N. A., Ivanov, A., Brock, C., Drotar, M. E., Nixon, C., Clark, W., Sansom, O. J., Anderson, K. I., King, A., Blyth, K., and Adams, P. D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Genes and Development
Publisher:Cold Spring Harbor Laboratory Press
ISSN:0890-9369
ISSN (Online):1549-5477
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Genes and Development 28(24):2712-2725
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
510446Epigenetics of Aging and Age-associated diseases : Epigenetic regulation of senescence and agingPeter AdamsNational Institute of Health (USA) (NIH(US))2P01AG031862-06RI CANCER SCIENCES
625581Senescence-associated chromatin changes a barrier to tumor progression.Peter AdamsCancer Research UK (CAN-RES-UK)C10652/A16566ICS - EPIGENETICS