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

Taranjit Singh Rai, John J. Cole, David M. Nelson, Dina Dikovskaya, William J. Faller, Maria Grazia Vizioli, Rachael N. Hewitt, Orchi Anannya, Tony McBryan, Indrani Manoharan, John Van Tuyn, Nicholas Morrice, Nikolay A. Pchelintsev, Andre Ivanov, Claire Brock, Mark E. Drotar, Colin Nixon, William Clark, Owen J. Sansom, Kurt I. Anderson & 3 others Ayala King, Karen Blyth, Peter D. Adams

Research output: Contribution to journalArticle

46 Citations (Scopus)

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.

LanguageEnglish
Pages2712-2725
Number of pages14
JournalGenes and Development
Volume28
Issue number24
DOIs
Publication statusPublished - 15 Dec 2014

Fingerprint

Chromatin
Histones
Neoplasms
Cell Aging
DNA Replication
Histone Chaperones
RNA Stability
Alternative Splicing
Oncogenes
Genes
Carcinogenesis
Messenger RNA

Keywords

  • Chromatin
  • Dynamic
  • H4K16ac
  • HIRA
  • Senescence
  • Tumor suppression

Cite this

Rai, T. S., Cole, J. J., Nelson, D. M., Dikovskaya, D., Faller, W. J., Vizioli, M. G., ... Adams, P. D. (2014). HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of Neoplasia. Genes and Development, 28(24), 2712-2725. https://doi.org/10.1101/gad.247528.114
Rai, Taranjit Singh ; Cole, John J. ; Nelson, David M. ; Dikovskaya, Dina ; Faller, William J. ; Vizioli, Maria Grazia ; Hewitt, Rachael N. ; Anannya, Orchi ; McBryan, Tony ; Manoharan, Indrani ; Van Tuyn, John ; Morrice, Nicholas ; Pchelintsev, Nikolay A. ; Ivanov, Andre ; Brock, Claire ; Drotar, Mark E. ; Nixon, Colin ; Clark, William ; Sansom, Owen J. ; Anderson, Kurt I. ; King, Ayala ; Blyth, Karen ; Adams, Peter D. / HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of Neoplasia. In: Genes and Development. 2014 ; Vol. 28, No. 24. pp. 2712-2725.
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Rai, TS, Cole, JJ, Nelson, DM, Dikovskaya, D, Faller, WJ, Vizioli, MG, Hewitt, RN, Anannya, O, McBryan, T, Manoharan, I, Van Tuyn, J, Morrice, N, Pchelintsev, NA, Ivanov, A, Brock, C, Drotar, ME, Nixon, C, Clark, W, Sansom, OJ, Anderson, KI, King, A, Blyth, K & Adams, PD 2014, 'HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of Neoplasia', Genes and Development, vol. 28, no. 24, pp. 2712-2725. https://doi.org/10.1101/gad.247528.114

HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of Neoplasia. / Rai, Taranjit Singh; Cole, John J.; Nelson, David M.; Dikovskaya, Dina; Faller, William J.; Vizioli, Maria Grazia; Hewitt, Rachael N.; Anannya, Orchi; McBryan, Tony; Manoharan, Indrani; Van Tuyn, John; Morrice, Nicholas; Pchelintsev, Nikolay A.; Ivanov, Andre; Brock, Claire; Drotar, Mark E.; Nixon, Colin; Clark, William; Sansom, Owen J.; Anderson, Kurt I.; King, Ayala; Blyth, Karen; Adams, Peter D.

In: Genes and Development, Vol. 28, No. 24, 15.12.2014, p. 2712-2725.

Research output: Contribution to journalArticle

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