Histone variants: critical determinants in tumour heterogeneity

Abstract

Malignant cell transformation could be considered as a series of cell reprogramming events driven by oncogenic transcription factors and upstream signalling pathways. Chromatin plasticity and dynamics are critical determinants in the control of cell reprograming. An increase in chromatin dynamics could therefore constitute an essential step in driving oncogenesis and in generating tumour cell heterogeneity, which is indispensable for the selection of aggressive properties, including the ability of cells to disseminate and acquire resistance to treatments. Histone supply and dosage, as well as histone variants, are the best-known regulators of chromatin dynamics. By facilitating cell reprogramming, histone under-dosage and histone variants should also be crucial in cell transformation and tumour metastasis. Here we summarize and discuss our knowledge of the role of histone supply and histone variants in chromatin dynamics and their ability to enhance oncogenic cell reprogramming and tumour heterogeneity.

Keywords

cancer-testis / TH2B / TH2A / H1T / H1.0 / H1F0 / linker histones

References

[1] Assenov Y, Brocks D, Gerhäuser C. Intratumor heterogeneity in epigenetic patterns. Semin Cancer Biol 2018; 51: 12–21

[2] Mazor T, Pankov A, Song JS, Costello JF. Intratumoral heterogeneity of the epigenome. Cancer Cell 2016; 29(4): 440–451

[3] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144(5): 646–674

[4] Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126(4): 663–676

[5] Ecker S, Pancaldi V, Valencia A, Beck S, Paul DS. Epigenetic and transcriptional variability shape phenotypic plasticity. BioEssays 2018; 40(2): 1700148

[6] Puisieux A, Pommier RM, Morel AP, Lavial F. Cellular pliancy and the multistep process of tumorigenesis. Cancer Cell 2018; 33(2): 164–172

[7] Decottignies A, d’Adda di Fagagna F. Epigenetic alterations associated with cellular senescence: a barrier against tumorigenesis or a red carpet for cancer? Semin Cancer Biol 2011; 21(6): 360–366

[8] De Carvalho DD, You JS, Jones PA. DNA methylation and cellular reprogramming. Trends Cell Biol 2010; 20(10): 609–617

[9] Becker JS, Nicetto D, Zaret KS. H3K9me3-dependent heterochromatin: barrier to cell fate changes. Trends Genet 2016; 32(1): 29–41

[10] Burton A, Torres-Padilla ME. Chromatin dynamics in the regulation of cell fate allocation during early embryogenesis. Nat Rev Mol Cell Biol 2014; 15(11): 723–734

[11] Apostolou E, Hochedlinger K. Chromatin dynamics during cellular reprogramming. Nature 2013; 502(7472): 462–471

[12] Cheloufi S, Hochedlinger K. Emerging roles of the histone chaperone CAF-1 in cellular plasticity. Curr Opin Genet Dev 2017; 46: 83–94

[13] Hauer MH, Gasser SM. Chromatin and nucleosome dynamics in DNA damage and repair. Genes Dev 2017; 31(22): 2204–2221

[14] Hoghoughi N, Barral S, Vargas A, Rousseaux S, Khochbin S. Histone variants: essential actors in male genome programming. J Biochem 2018; 163(2): 97–103

[15] Gaume X, Torres-Padilla ME. Regulation of reprogramming and cellular plasticity through histone exchange and histone variant incorporation. Cold Spring Harb Symp Quant Biol 2015; 80: 165–175

[16] Yang P, Wu W, Macfarlan TS. Maternal histone variants and their chaperones promote paternal genome activation and boost somatic cell reprogramming. BioEssays 2015; 37(1): 52–59

[17] Gurard-Levin ZA, Quivy JP, Almouzni G. Histone chaperones: assisting histone traffic and nucleosome dynamics. Annu Rev Biochem 2014; 83(1): 487–517

[18] Cheloufi S, Elling U, Hopfgartner B, Jung YL, Murn J, Ninova M, Hubmann M, Badeaux AI, Euong Ang C, Tenen D, Wesche DJ, Abazova N, Hogue M, Tasdemir N, Brumbaugh J, Rathert P, Jude J, Ferrari F, Blanco A, Fellner M, Wenzel D, Zinner M, Vidal SE, Bell O, Stadtfeld M, Chang HY, Almouzni G, Lowe SW, Rinn J, Wernig M, Aravin A, Shi Y, Park PJ, Penninger JM, Zuber J, Hochedlinger K. The histone chaperone CAF-1 safeguards somatic cell identity. Nature 2015; 528(7581): 218–224

[19] Ishiuchi T, Enriquez-Gasca R, Mizutani E, Bošković A, Ziegler-Birling C, Rodriguez-Terrones D, Wakayama T, Vaquerizas JM, Torres-Padilla ME. Early embryonic-like cells are induced by downregulating replication-dependent chromatin assembly. Nat Struct Mol Biol 2015; 22(9): 662–671

[20] Rivera-Casas C, Gonzalez-Romero R, Cheema MS, Ausió J, Eirín-López JM. The characterization of macroH2A beyond vertebrates supports an ancestral origin and conserved role for histone variants in chromatin. Epigenetics 2016; 11(6): 415–425

[21] Soboleva TA, Nekrasov M, Pahwa A, Williams R, Huttley GA, Tremethick DJ. A unique H2A histone variant occupies the transcriptional start site of active genes. Nat Struct Mol Biol 2011; 19(1): 25–30

[22] Barral S, Morozumi Y, Tanaka H, Montellier E, Govin J, de Dieuleveult M, Charbonnier G, Couté Y, Puthier D, Buchou T, Boussouar F, Urahama T, Fenaille F, Curtet S, Héry P, Fernandez-Nunez N, Shiota H, Gérard M, Rousseaux S, Kurumizaka H, Khochbin S. Histone variant H2A.L.2 guides transition protein-dependent protamine assembly in male germ cells. Mol Cell 2017; 66(1): 89–101.e8

[23] Pasque V, Gillich A, Garrett N, Gurdon JB. Histone variant macroH2A confers resistance to nuclear reprogramming. EMBO J 2011; 30(12): 2373–2387

[24] Shinagawa T, Takagi T, Tsukamoto D, Tomaru C, Huynh LM, Sivaraman P, Kumarevel T, Inoue K, Nakato R, Katou Y, Sado T, Takahashi S, Ogura A, Shirahige K, Ishii S. Histone variants enriched in oocytes enhance reprogramming to induced pluripotent stem cells. Cell Stem Cell 2014; 14(2): 217–227

[25] Quénet D. Histone variants and disease. Int Rev Cell Mol Biol 2018; 335: 1–39

[26] Rousseaux S, Debernardi A, Jacquiau B, Vitte AL, Vesin A, Nagy-Mignotte H, Moro-Sibilot D, Brichon PY, Lantuejoul S, Hainaut P, Laffaire J, de Reyniès A, Beer DG, Timsit JF, Brambilla C, Brambilla E, Khochbin S. Ectopic activation of germline and placental genes identifies aggressive metastasis-prone lung cancers. Sci Transl Med 2013; 5(186): 186ra66

[27] Govin J, Caron C, Rousseaux S, Khochbin S. Testis-specific histone H3 expression in somatic cells. Trends Biochem Sci 2005; 30(7): 357–359

[28] Mohammad F, Helin K. Oncohistones: drivers of pediatric cancers. Genes Dev 2017; 31(23-24): 2313–2324

[29] Gaucher J, Reynoird N, Montellier E, Boussouar F, Rousseaux S, Khochbin S. From meiosis to postmeiotic events: the secrets of histone disappearance. FEBS J 2010; 277(3): 599–604

[30] Ueda J, Harada A, Urahama T, Machida S, Maehara K, Hada M, Makino Y, Nogami J, Horikoshi N, Osakabe A, Taguchi H, Tanaka H, Tachiwana H, Yao T, Yamada M, Iwamoto T, Isotani A, Ikawa M, Tachibana T, Okada Y, Kimura H, Ohkawa Y, Kurumizaka H, Yamagata K. Testis-specific histone variant H3t gene is essential for entry into spermatogenesis. Cell Reports 2017; 18(3): 593–600

[31] Tachiwana H, Kagawa W, Osakabe A, Kawaguchi K, Shiga T, Hayashi-Takanaka Y, Kimura H, Kurumizaka H. Structural basis of instability of the nucleosome containing a testis-specific histone variant, human H3T. Proc Natl Acad Sci USA 2010; 107(23): 10454–10459

[32] Zhou J, Fan JY, Rangasamy D, Tremethick DJ. The nucleosome surface regulates chromatin compaction and couples it with transcriptional repression. Nat Struct Mol Biol 2007; 14(11): 1070–1076

[33] Montellier E, Boussouar F, Rousseaux S, Zhang K, Buchou T, Fenaille F, Shiota H, Debernardi A, Héry P, Curtet S, Jamshidikia M, Barral S, Holota H, Bergon A, Lopez F, Guardiola P, Pernet K, Imbert J, Petosa C, Tan M, Zhao Y, Gérard M, Khochbin S. Chromatin-to-nucleoprotamine transition is controlled by the histone H2B variant TH2B. Genes Dev 2013; 27(15): 1680–1692

[34] Shinagawa T, Huynh LM, Takagi T, Tsukamoto D, Tomaru C, Kwak HG, Dohmae N, Noguchi J, Ishii S. Disruption of Th2a and Th2b genes causes defects in spermatogenesis. Development 2015; 142(7): 1287–1292

[35] Iuso D, Czernik M, Toschi P, Fidanza A, Zacchini F, Feil R, Curtet S, Buchou T, Shiota H, Khochbin S, Ptak GE, Loi P. Exogenous expression of human protamine 1 (hPrm1) remodels fibroblast nuclei into spermatid-like structures. Cell Reports 2015; 13(9): 1765–1771

[36] Chodaparambil JV, Barbera AJ, Lu X, Kaye KM, Hansen JC, Luger K. A charged and contoured surface on the nucleosome regulates chromatin compaction. Nat Struct Mol Biol 2007; 14(11): 1105–1107

[37] Luger K, Mäder AW, Richmond RK, Sargent DF, Richmond TJ. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 1997; 389(6648): 251–260

[38] Molaro A, Young JM, Malik HS. Evolutionary origins and diversification of testis-specific short histone H2A variants in mammals. Genome Res 2018; 28(4): 460–473

[39] Bao Y, Konesky K, Park YJ, Rosu S, Dyer PN, Rangasamy D, Tremethick DJ, Laybourn PJ, Luger K. Nucleosomes containing the histone variant H2A.Bbd organize only 118 base pairs of DNA. EMBO J 2004; 23(16): 3314–3324

[40] Syed SH, Boulard M, Shukla MS, Gautier T, Travers A, Bednar J, Faivre-Moskalenko C, Dimitrov S, Angelov D. The incorporation of the novel histone variant H2AL2 confers unusual structural and functional properties of the nucleosome. Nucleic Acids Res 2009; 37(14): 4684–4695

[41] Winkler C, Steingrube DS, Altermann W, Schlaf G, Max D, Kewitz S, Emmer A, Kornhuber M, Banning-Eichenseer U, Staege MS. Hodgkin’s lymphoma RNA-transfected dendritic cells induce cancer/testis antigen-specific immune responses. Cancer Immunol Immunother 2012; 61(10): 1769–1779

[42] Sansoni V, Casas-Delucchi CS, Rajan M, Schmidt A, Bönisch C, Thomae AW, Staege MS, Hake SB, Cardoso MC, Imhof A. The histone variant H2A.Bbd is enriched at sites of DNA synthesis. Nucleic Acids Res 2014; 42(10): 6405–6420

[43] Khochbin S. Histone H1 diversity: bridging regulatory signals to linker histone function. Gene 2001; 271(1): 1–12

[44] Peretti M, Khochbin S. The evolution of the differentiation-specific histone H1 gene basal promoter. J Mol Evol 1997; 44(2): 128–134

[45] Rousseau D, Khochbin S, Gorka C, Lawrence JJ. Regulation of histone H1(0) accumulation during induced differentiation of murine erythroleukemia cells. J Mol Biol 1991; 217(1): 85–92

[46] Rousseau D, Khochbin S, Gorka C, Lawrence JJ. Induction of H1(0)-gene expression in B16 murine melanoma cells. Eur J Biochem 1992; 208(3): 775–779

[47] Khochbin S, Wolffe AP. Developmental regulation and butyrate-inducible transcription of the Xenopus histone H1(0) promoter. Gene 1993; 128(2): 173–180

[48] Seigneurin D, Grunwald D, Lawrence JJ, Khochbin S. Developmentally regulated chromatin acetylation and histone H1(0) accumulation. Int J Dev Biol 1995; 39(4): 597–603

[49] Grunwald D, Lawrence JJ, Khochbin S. Accumulation of histone H1(0) during early Xenopus laevis development. Exp Cell Res 1995; 218(2): 586–595

[50] Izzo A, Ziegler-Birling C, Hill PWS, Brondani L, Hajkova P, Torres-Padilla ME, Schneider R. Dynamic changes in H1 subtype composition during epigenetic reprogramming. J Cell Biol 2017; jcb.201611012

[51] Torres CM, Biran A, Burney MJ, Patel H, Henser-Brownhill T, Cohen AS, Li Y, Ben-Hamo R, Nye E, Spencer-Dene B, Chakravarty P, Efroni S, Matthews N, Misteli T, Meshorer E, Scaffidi P. The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity. Science 2016; 353(6307): aaf1644

[52] Gorka C, Lawrence JJ, Khochbin S. Variation of H1(0) content throughout the cell cycle in regenerating rat liver. Exp Cell Res 1995; 217(2): 528–533

[53] Khochbin S, Wolffe AP. Developmentally regulated expression of linker-histone variants in vertebrates. Eur J Biochem 1994; 225(2): 501–510

[54] Grunwald D, Khochbin S, Lawrence JJ. Cell cycle-related accumulation of H1(0) mRNA: induction in murine erythroleukemia cells. Exp Cell Res 1991; 194(2): 174–179

[55] Brocard MP, Triebe S, Peretti M, Doenecke D, Khochbin S. Characterization of the two H1(zero)-encoding genes from Xenopus laevis. Gene 1997; 189(1): 127–134

[56] Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E, Shad S, Hasz R, Walters G, Garcia F, Young N, Foster B, Moser M, Karasik E, Gillard B, Ramsey K, Sullivan S, Bridge J, Magazine H, Syron J, Fleming J, Siminoff L, Traino H, Mosavel M, Barker L, Jewell S, Rohrer D, Maxim D, Filkins D, Harbach P, Cortadillo E, Berghuis B, Turner L, Hudson E, Feenstra K, Sobin L, Robb J, Branton P, Korzeniewski G, Shive C, Tabor D, Qi L, Groch K, Nampally S, Buia S, Zimmerman A, Smith A, Burges R, Robinson K, Valentino K, Bradbury D, Cosentino M, Diaz-Mayoral N, Kennedy M, Engel T, Williams P, Erickson K, Ardlie K, Winckler W, Getz G, DeLuca D, MacArthur D, Kellis M, Thomson A, Young T, Gelfand E, Donovan M, Meng Y, Grant G, Mash D, Marcus Y, Basile M, Liu J, Zhu J, Tu Z, Cox NJ, Nicolae DL, Gamazon ER, Im HK, Konkashbaev A, Pritchard J, Stevens M, Flutre T, Wen X, Dermitzakis ET, Lappalainen T, Guigo R, Monlong J, Sammeth M, Koller D, Battle A, Mostafavi S, McCarthy M, Rivas M, Maller J, Rusyn I, Nobel A, Wright F, Shabalin A, Feolo M, Sharopova N, Sturcke A, Paschal J, Anderson JM, Wilder EL, Derr LK, Green ED, Struewing JP, Temple G, Volpi S, Boyer JT, Thomson EJ, Guyer MS, Ng C, Abdallah A, Colantuoni D, Insel TR, Koester SE, Little AR, Bender PK, Lehner T, Yao Y, Compton CC, Vaught JB, Sawyer S, Lockhart NC, Demchok J, Moore HF; GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat Genet 2013; 45(6): 580–585

[57] Peng L, Bian XW, Li DK, Xu C, Wang GM, Xia QY, Xiong Q. Large-scale RNA-seq transcriptome analysis of 4043 cancers and 548 normal tissue controls across 12 TCGA cancer types. Sci Rep 2015; 5(1): 13413

[58] Djureinovic D, Hallström BM, Horie M, Mattsson JSM, La Fleur L, Fagerberg L, Brunnström H, Lindskog C, Madjar K, Rahnenführer J, Ekman S, Ståhle E, Koyi H, Brandén E, Edlund K, Hengstler JG, Lambe M, Saito A, Botling J, Pontén F, Uhlén M, Micke P. Profiling cancer testis antigens in non-small-cell lung cancer. JCI Insight 2016; 1(10): e86837

Acknowledgements

This review was prepared in frame of “Pitcher” research program on tumour heterogeneity (Plan Cancer: No. C16012CS). WT is a post-doctoral fellow on this program. Research in SK and JM is supported by Cai Yuanpei program and by the “Pôle Sino-Français des Sciences du Vivant et Genomique.”

ƒSK laboratory is also supported by a grant from “Foundation pour la Recherche Medicale (FRM)” “analyse bio-informatique pour la recherche en biologie” program, as well as by ANR Episperm3 program. Additional support is from: the “Université Grenoble Alpes” ANR-15-IDEX-02 LIFE and SYMER programs as well as from Fondation ARC “Canc’air” project (No. RAC16042CLA), Plan Cancer (No. CH7-INS15B66).

Compliance with ethics guidelines

Tao Wang, Florent Chuffart, Ekaterina Bourova-Flin, Jin Wang, Jianqing Mi, Sophie Rousseaux, and Saadi Khochbin declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the appropriate credit is given to the original author(s) and the source, and a link is provided to the Creative Commons license, which indicates if changes are made.

RIGHTS & PERMISSIONS

2018 The Author(s) 2018. This article is published with open access at link.springer.com and journal.hep.com.cn