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

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.

Original languageEnglish
Pages (from-to)2712-25
Number of pages14
JournalGenes & 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

  • Animals
  • Antineoplastic Agents, Hormonal
  • Carcinogenesis
  • Cell Aging
  • Cell Cycle Proteins
  • Cell Line
  • Cell Proliferation
  • Chromatin
  • Female
  • Gene Expression Regulation
  • Genetic Markers
  • Histone Chaperones
  • Histones
  • Humans
  • Male
  • Mice
  • Papilloma
  • Skin Neoplasms
  • Tamoxifen
  • Transcription Factors

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 & Development, 28(24), 2712-25. 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 & Development. 2014 ; Vol. 28, No. 24. pp. 2712-25.
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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 & Development, vol. 28, no. 24, pp. 2712-25. 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 & Development, Vol. 28, No. 24, 15.12.2014, p. 2712-25.

Research output: Contribution to journalArticle

TY - JOUR

T1 - HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia

AU - Rai, Taranjit Singh

AU - Cole, John J

AU - Nelson, David M

AU - Dikovskaya, Dina

AU - Faller, William J

AU - Vizioli, Maria Grazia

AU - Hewitt, Rachael N

AU - Anannya, Orchi

AU - McBryan, Tony

AU - Manoharan, Indrani

AU - van Tuyn, John

AU - Morrice, Nicholas

AU - Pchelintsev, Nikolay A

AU - Ivanov, Andre

AU - Brock, Claire

AU - Drotar, Mark E

AU - Nixon, Colin

AU - Clark, William

AU - Sansom, Owen J

AU - Anderson, Kurt I

AU - King, Ayala

AU - Blyth, Karen

AU - Adams, Peter D

N1 - © 2014 Rai et al.; Published by Cold Spring Harbor Laboratory Press.

PY - 2014/12/15

Y1 - 2014/12/15

N2 - 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.

AB - 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.

KW - Animals

KW - Antineoplastic Agents, Hormonal

KW - Carcinogenesis

KW - Cell Aging

KW - Cell Cycle Proteins

KW - Cell Line

KW - Cell Proliferation

KW - Chromatin

KW - Female

KW - Gene Expression Regulation

KW - Genetic Markers

KW - Histone Chaperones

KW - Histones

KW - Humans

KW - Male

KW - Mice

KW - Papilloma

KW - Skin Neoplasms

KW - Tamoxifen

KW - Transcription Factors

U2 - 10.1101/gad.247528.114

DO - 10.1101/gad.247528.114

M3 - Article

VL - 28

SP - 2712

EP - 2725

JO - Genes & Development

JF - Genes & Development

SN - 0890-9369

IS - 24

ER -