title: HIRA orchestrates a dynamic chromatin landscape in senescence and is required for suppression of neoplasia.
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.
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom; Institute of Biomedical and Environmental Health Research, University of West of Scotland, Paisley PA1 2BE, United Kingdom p.adams@beatson.gla.ac.uk taranjitsingh.rai@uws.ac.uk.
authors.forename: Taranjit Singh
authors.initials: TS
authors.lastname: Rai
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom;
authors.forename: John J
authors.initials: JJ
authors.lastname: Cole
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom;
authors.forename: David M
authors.initials: DM
authors.lastname: Nelson
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom;
authors.forename: Dina
authors.initials: D
authors.lastname: Dikovskaya
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom;
authors.forename: William J
authors.initials: WJ
authors.lastname: Faller
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom;
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Vizioli
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom;
authors.forename: Rachael N
authors.initials: RN
authors.lastname: Hewitt
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom;
authors.forename: Orchi
authors.initials: O
authors.lastname: Anannya
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom;
authors.forename: Tony
authors.initials: T
authors.lastname: McBryan
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom;
authors.forename: Indrani
authors.initials: I
authors.lastname: Manoharan
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom;
authors.forename: John
authors.initials: J
authors.lastname: van Tuyn
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom;
authors.forename: Nicholas
authors.initials: N
authors.lastname: Morrice
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom;
authors.forename: Nikolay A
authors.initials: NA
authors.lastname: Pchelintsev
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom;
authors.forename: Andre
authors.initials: A
authors.lastname: Ivanov
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom;
authors.forename: Claire
authors.initials: C
authors.lastname: Brock
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom;
authors.forename: Mark E
authors.initials: ME
authors.lastname: Drotar
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom;
authors.forename: Colin
authors.initials: C
authors.lastname: Nixon
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom;
authors.forename: William
authors.initials: W
authors.lastname: Clark
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom;
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom;
authors.forename: Kurt I
authors.initials: KI
authors.lastname: Anderson
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom;
authors.forename: Ayala
authors.initials: A
authors.lastname: King
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom;
authors.forename: Karen
authors.initials: K
authors.lastname: Blyth
authors.affiliation: Beatson Institute for Cancer Research, Bearsden, Glasgow G61 1BD, United Kingdom; Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G61 1BD, United Kingdom; p.adams@beatson.gla.ac.uk taranjitsingh.rai@uws.ac.uk.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Adams
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D002843:Chromatin / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005819:Genetic Markers; D056488:Histone Chaperones / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D010212:Papilloma / Q000473:pathology; D012878:Skin Neoplasms / Q000473:pathology; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D018797:Cell Cycle Proteins; D002843:Chromatin; D005819:Genetic Markers; C086057:HIRA protein, human; C484187:Hira protein, mouse; D056488:Histone Chaperones; D006657:Histones; D014157:Transcription Factors; D013629:Tamoxifen
keywords: H4K16ac; HIRA; chromatin; dynamic; senescence; tumor suppression