Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Every amino acid matters: essential contributions of histone variants to mammalian development and disease

Nature Reviews Genetics volume 15, pages 259–271 (2014)Cite this article

Subjects

Key Points

  • Histone variants introduce small sequence variations into the eukaryotic epigenome to affect numerous aspects of chromatin structural organization, nucleosomal dynamics and transcription.

  • Histone variants have crucial roles during mammalian germ cell development and differentiation.

  • The exchange of histone variants is required to form normal patterns of zygotic and embryonic development.

  • Alterations in histone variant expression and/or activity have been directly linked to various forms of human disease, including cancer.

Abstract

Despite a conserved role for histones as general DNA packaging agents, it is now clear that another key function of these proteins is to confer variations in chromatin structure to ensure dynamic patterns of transcriptional regulation in eukaryotes. The incorporation of histone variants is particularly important to this process. Recent knockdown and knockout studies in various cellular systems, as well as direct mutational evidence from human cancers, now suggest a crucial role for histone variant regulation in processes as diverse as differentiation and proliferation, meiosis and nuclear reprogramming. In this Review, we provide an overview of histone variants in the context of their unique functions during mammalian germ cell and embryonic development, and examine the consequences of aberrant histone variant regulation in human disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Human core and linker histone variants.
Figure 2: Structural characterization of H3.3 in complex with DAXX: implications for chaperone- specific histone variant deposition.
Figure 3: Histone variant exchange in post-replicative cells.
Figure 4: H3.3 variant mutations in brain gliomas: direct evidence that 'every amino acid matters'.

Similar content being viewed by others

References

  1. Skene, P. J. & Henikoff, S. Histone variants in pluripotency and disease. Development 140, 2513–2524 (2013).

    CAS  PubMed  Google Scholar 

  2. Chen, P., Zhao, J. & Li, G. Histone variants in development and diseases. J. Genet. Genom. 40, 355–365 (2013).

    CAS  Google Scholar 

  3. Filipescu, D., Szenker, E. & Almouzni, G. Developmental roles of histone H3 variants and their chaperones. Trends Genet. 29, 630–640 (2013).

    CAS  PubMed  Google Scholar 

  4. Talbert, P. B. & Henikoff, S. Histone variants — ancient wrap artists of the epigenome. Nature Rev. Mol. Cell Biol. 11, 264–275 (2010).

    CAS  Google Scholar 

  5. Elsasser, S. J. et al. DAXX envelops a histone H3.3–H4 dimer for H3.3-specific recognition. Nature 491, 560–565 (2012).

    PubMed  PubMed Central  Google Scholar 

  6. Ranjan, A. et al. Nucleosome-free region dominates histone acetylation in targeting SWR1 to promoters for H2A.Z replacement. Cell 154, 1232–1245 (2013).

    CAS  PubMed  Google Scholar 

  7. Yen, K., Vinayachandran, V. & Pugh, B. F. SWR-C and INO80 chromatin remodelers recognize nucleosome-free regions near +1 nucleosomes. Cell 154, 1246–1256 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Banaszynski, L. A., Allis, C. D. & Lewis, P. W. Histone variants in metazoan development. Dev. Cell 19, 662–674 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Drabent, B., Bode, C., Bramlage, B. & Doenecke, D. Expression of the mouse testicular histone gene H1t during spermatogenesis. Histochem. Cell Biol. 106, 247–251 (1996).

    CAS  PubMed  Google Scholar 

  10. Martianov, I. et al. Polar nuclear localization of H1T2, a histone H1 variant, required for spermatid elongation and DNA condensation during spermiogenesis. Proc. Natl Acad. Sci. USA 102, 2808–2813 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Ishibashi, T. et al. H2A.Bbd: an X-chromosome-encoded histone involved in mammalian spermiogenesis. Nucleic Acids Res. 38, 1780–1789 (2010).

    CAS  PubMed  Google Scholar 

  12. Govin, J. et al. Pericentric heterochromatin reprogramming by new histone variants during mouse spermiogenesis. J. Cell Biol. 176, 283–294 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Zalensky, A. O. et al. Human testis/sperm-specific histone H2B (hTSH2B): molecular cloning and characterization. J. Biol. Chem. 277, 43474–43480 (2002).

    CAS  PubMed  Google Scholar 

  14. Witt, O., Albig, W. & Doenecke, D. Testis-specific expression of a novel human H3 histone gene. Exp. Cell Res. 229, 301–306 (1996).

    CAS  PubMed  Google Scholar 

  15. Schenk, R., Jenke, A., Zilbauer, M., Wirth, S. & Postberg, J. H3.5 is a novel hominid-specific histone H3 variant that is specifically expressed in the seminiferous tubules of human testes. Chromosoma 120, 275–285 (2011).

    CAS  PubMed  Google Scholar 

  16. Bao, Y. et al. Nucleosomes containing the histone variant H2A.Bbd organize only 118 base pairs of DNA. EMBO J. 23, 3314–3324 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Syed, S. H. et al. The incorporation of the novel histone variant H2AL2 confers unusual structural and functional properties of the nucleosome. Nucleic Acids Res. 37, 4684–4695 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Soboleva, T. A. et al. A unique H2A histone variant occupies the transcriptional start site of active genes. Nature Struct. Mol. Biol. 19, 25–30 (2012).

    CAS  Google Scholar 

  19. Li, A. et al. Characterization of nucleosomes consisting of the human testis/sperm-specific histone H2B variant (hTSH2B). Biochemistry 44, 2529–2535 (2005).

    CAS  PubMed  Google Scholar 

  20. Tachiwana, H. et al. Structural basis of instability of the nucleosome containing a testis-specific histone variant, human H3T. Proc. Natl Acad. Sci. USA 107, 10454–10459 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Montellier, E. et al. Chromatin-to-nucleoprotamine transition is controlled by the histone H2B variant TH2B. Genes Dev. 27, 1680–1692 (2013). This study is the first to show that TSH2B exchange is required for protamine replacement during spermatogenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Tolstorukov, M. Y. et al. Histone variant H2A.Bbd is associated with active transcription and mRNA processing in human cells. Mol. Cell 47, 596–607 (2012). This study illustrated that H2A.Bbd is enriched throughout active regions of the genome and forms a complex with both elongating RNA polymerase II and spliceosomal elements when stably expressed in HeLa cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Ioudinkova, E. S. et al. Distinct distribution of ectopically expressed histone variants H2A.Bbd and macroH2A in open and closed chromatin domains. PLoS ONE 7, e47157 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Hoyer-Fender, S., Costanzi, C. & Pehrson, J. R. Histone macroH2A1.2 is concentrated in the XY-body by the early pachytene stage of spermatogenesis. Exp. Cell Res. 258, 254–260 (2000).

    CAS  PubMed  Google Scholar 

  25. Mahadevaiah, S. K. et al. Recombinational DNA double-strand breaks in mice precede synapsis. Nature Genet. 27, 271–276 (2001).

    CAS  PubMed  Google Scholar 

  26. van der Heijden, G. W. et al. Chromosome-wide nucleosome replacement and H3.3 incorporation during mammalian meiotic sex chromosome inactivation. Nature Genet. 39, 251–258 (2007).

    CAS  PubMed  Google Scholar 

  27. Fernandez-Capetillo, O. et al. H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis. Dev. Cell 4, 497–508 (2003).

    CAS  PubMed  Google Scholar 

  28. Greaves, I. K., Rangasamy, D., Devoy, M., Marshall Graves, J. A. & Tremethick, D. J. The X and Y chromosomes assemble into H2A.Z-containing facultative heterochromatin following meiosis. Mol. Cell. Biol. 26, 5394–5405 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Hammoud, S. S. et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature 460, 473–478 (2009). This paper is the first to use genome-wide sequencing to identify targets of histone retention in human sperm, with a specific emphasis on histone modifications.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Erkek, S. et al. Molecular determinants of nucleosome retention at CpG-rich sequences in mouse spermatozoa. Nature Struct. Mol. Biol. 20, 868–875 (2013).

    CAS  Google Scholar 

  31. Brykczynska, U. et al. Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa. Nature Struct. Mol. Biol. 17, 679–687 (2010).

    CAS  Google Scholar 

  32. Hammoud, S. S. et al. Genome-wide analysis identifies changes in histone retention and epigenetic modifications at developmental and imprinted gene loci in the sperm of infertile men. Hum. Reprod. 26, 2558–2569 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Tanaka, M., Hennebold, J. D., Macfarlane, J. & Adashi, E. Y. A mammalian oocyte-specific linker histone gene H1oo: homology with the genes for the oocyte-specific cleavage stage histone (cs-H1) of sea urchin and the B4/H1M histone of the frog. Development 128, 655–664 (2001).

    CAS  PubMed  Google Scholar 

  34. Torres-Padilla, M. E., Bannister, A. J., Hurd, P. J., Kouzarides, T. & Zernicka-Goetz, M. Dynamic distribution of the replacement histone variant H3.3 in the mouse oocyte and preimplantation embryos. Int. J. Dev. Biol. 50, 455–461 (2006).

    CAS  PubMed  Google Scholar 

  35. Akiyama, T., Suzuki, O., Matsuda, J. & Aoki, F. Dynamic replacement of histone H3 variants reprograms epigenetic marks in early mouse embryos. PLoS Genet. 7, e1002279 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Chang, C. C. et al. A maternal store of macroH2A is removed from pronuclei prior to onset of somatic macroH2A expression in preimplantation embryos. Dev. Biol. 278, 367–380 (2005).

    CAS  PubMed  Google Scholar 

  37. Santenard, A. et al. Heterochromatin formation in the mouse embryo requires critical residues of the histone variant H3.3. Nature Cell Biol. 12, 853–862 (2010).

    CAS  PubMed  Google Scholar 

  38. Orsi, G. A. et al. Drosophila Yemanuclein and HIRA cooperate for de novo assembly of H3.3-containing nucleosomes in the male pronucleus. PLoS Genet. 9, e1003285 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Loppin, B. et al. The histone H3.3 chaperone HIRA is essential for chromatin assembly in the male pronucleus. Nature 437, 1386–1390 (2005). This work is the first to show that HIRA specifically incorporates H3.3 into paternal zygotic chromatin prior to the first round of DNA replication.

    CAS  PubMed  Google Scholar 

  40. Costanzi, C., Stein, P., Worrad, D. M., Schultz, R. M. & Pehrson, J. R. Histone macroH2A1 is concentrated in the inactive X chromosome of female preimplantation mouse embryos. Development 127, 2283–2289 (2000).

    CAS  PubMed  Google Scholar 

  41. Tang, M. C., Jacobs, S. A., Wong, L. H. & Mann, J. R. Conditional allelic replacement applied to genes encoding the histone variant H3.3 in the mouse. Genesis 51, 142–146 (2013).

    CAS  PubMed  Google Scholar 

  42. Couldrey, C., Carlton, M. B., Nolan, P. M., Colledge, W. H. & Evans, M. J. A retroviral gene trap insertion into the histone 3.3A gene causes partial neonatal lethality, stunted growth, neuromuscular deficits and male sub-fertility in transgenic mice. Hum. Mol. Genet. 8, 2489–2495 (1999).

    CAS  PubMed  Google Scholar 

  43. Bush, K. M. et al. Endogenous mammalian histone H3.3 exhibits chromatin-related functions during development. Epigenetics Chromatin 6, 7 (2013). This paper provides the first evidence that complete knockout of one gene copy encoding H3.3 ( H3f3b ) results in severe developmental deficits in mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Lin, C. J., Conti, M. & Ramalho-Santos, M. Histone variant H3.3 maintains a decondensed chromatin state essential for mouse preimplantation development. Development 140, 3624–3634 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Banaszynski, L. A. et al. Hira-dependent histone H3.3 deposition facilitates PRC2 recruitment at developmental loci in ES cells. Cell 155, 107–120 (2013).

    CAS  PubMed  Google Scholar 

  46. Hodl, M. & Basler, K. Transcription in the absence of histone H3.3. Curr. Biol. 19, 1221–1226 (2009). This study reveals that canonical H3.2 can fully compensate for H3.3 in D. melanogaster . These findings need to be verified in a mammalian model system.

    CAS  PubMed  Google Scholar 

  47. Sakai, A., Schwartz, B. E., Goldstein, S. & Ahmad, K. Transcriptional and developmental functions of the H3.3 histone variant in Drosophila. Curr. Biol. 19, 1816–1820 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Hodl, M. & Basler, K. Transcription in the absence of histone H3.2 and H3K4 methylation. Curr. Biol. 22, 2253–2257 (2012).

    CAS  PubMed  Google Scholar 

  49. Eirin-Lopez, J. M., Gonzalez-Romero, R., Dryhurst, D., Ishibashi, T. & Ausio, J. The evolutionary differentiation of two histone H2A.Z variants in chordates (H2A.Z-1 and H2A.Z-2) is mediated by a stepwise mutation process that affects three amino acid residues. BMC Evol. Biol. 9, 31 (2009).

    PubMed  PubMed Central  Google Scholar 

  50. Faast, R. et al. Histone variant H2A.Z is required for early mammalian development. Curr. Biol. 11, 1183–1187 (2001).

    CAS  PubMed  Google Scholar 

  51. Hu, G. et al. H2A.Z facilitates access of active and repressive complexes to chromatin in embryonic stem cell self-renewal and differentiation. Cell Stem Cell 12, 180–192 (2013).

    CAS  PubMed  Google Scholar 

  52. Creyghton, M. P. et al. H2AZ is enriched at Polycomb complex target genes in ES cells and is necessary for lineage commitment. Cell 135, 649–661 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Wiedemann, S. M. et al. Identification and characterization of two novel primate-specific histone H3 variants, H3.X and H3.Y. J. Cell Biol. 190, 777–791 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Chen, P. et al. H3.3 actively marks enhancers and primes gene transcription via opening higher-ordered chromatin. Genes Dev. 27, 2109–2124 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Jin, C. et al. H3.3/H2A.Z double variant-containing nucleosomes mark 'nucleosome-free regions' of active promoters and other regulatory regions. Nature Genet. 41, 941–945 (2009).

    CAS  PubMed  Google Scholar 

  56. Nekrasov, M. et al. Histone H2A.Z inheritance during the cell cycle and its impact on promoter organization and dynamics. Nature Struct. Mol. Biol. 19, 1076–1083 (2012). This paper shows that unstable nucleosomes located at the TSS are heterotypic with respect to H2A (that is, H2A.Z–H2A), which increases instability to an already unstable environment that is occupied by two variants (for example, H2A.Z–H3.3).

    CAS  Google Scholar 

  57. Costanzi, C. & Pehrson, J. R. Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals. Nature 393, 599–601 (1998).

    CAS  PubMed  Google Scholar 

  58. Buschbeck, M. et al. The histone variant macroH2A is an epigenetic regulator of key developmental genes. Nature Struct. Mol. Biol. 16, 1074–1079 (2009).

    CAS  Google Scholar 

  59. Gamble, M. J., Frizzell, K. M., Yang, C., Krishnakumar, R. & Kraus, W. L. The histone variant macroH2A1 marks repressed autosomal chromatin, but protects a subset of its target genes from silencing. Genes Dev. 24, 21–32 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Celeste, A. et al. Genomic instability in mice lacking histone H2AX. Science 296, 922–927 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Bassing, C. H. et al. Increased ionizing radiation sensitivity and genomic instability in the absence of histone H2AX. Proc. Natl Acad. Sci. USA 99, 8173–8178 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Celeste, A. et al. H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell 114, 371–383 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Bassing, C. H. et al. Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114, 359–370 (2003).

    CAS  PubMed  Google Scholar 

  64. Izzo, A. et al. The genomic landscape of the somatic linker histone subtypes H1.1 to H1.5 in human cells. Cell Rep. 3, 2142–2154 (2013).

    CAS  PubMed  Google Scholar 

  65. Lu, X. et al. Drosophila H1 regulates the genetic activity of heterochromatin by recruitment of Su(var)3-9. Science 340, 78–81 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Cao, K. et al. High-resolution mapping of H1 linker histone variants in embryonic stem cells. PLoS Genet. 9, e1003417 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Morin, R. D. et al. Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing. Blood 122, 1256–1265 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Morin, R. D. et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature 476, 298–303 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Okosun, J. et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nature Genet. 46, 176–181 (2014).

    CAS  PubMed  Google Scholar 

  70. Pina, B. & Suau, P. Changes in histones H2A and H3 variant composition in differentiating and mature rat brain cortical neurons. Dev. Biol. 123, 51–58 (1987).

    CAS  PubMed  Google Scholar 

  71. Toyama, B. H. et al. Identification of long-lived proteins reveals exceptional stability of essential cellular structures. Cell 154, 971–982 (2013). This study uses metabolic pulse-chase labelling in rats to show that canonical H3 proteins (for example, H3.1) are highly stable in adult neural chromatin.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Hake, S. B. et al. Expression patterns and post-translational modifications associated with mammalian histone H3 variants. J. Biol. Chem. 281, 559–568 (2006).

    CAS  PubMed  Google Scholar 

  73. Hake, S. B. & Allis, C. D. Histone H3 variants and their potential role in indexing mammalian genomes: the “H3 barcode hypothesis”. Proc. Natl Acad. Sci. USA 103, 6428–6435 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Bernstein, E. & Hake, S. B. The nucleosome: a little variation goes a long way. Biochem. Cell Biol. 84, 505–517 (2006).

    CAS  PubMed  Google Scholar 

  75. Michod, D. et al. Calcium-dependent dephosphorylation of the histone chaperone DAXX regulates H3.3 loading and transcription upon neuronal activation. Neuron 74, 122–135 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Najmabadi, H. et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 478, 57–63 (2011).

    CAS  PubMed  Google Scholar 

  77. Cox, S. G. et al. An essential role of variant histone H3.3 for ectomesenchyme potential of the cranial neural crest. PLoS Genet. 8, e1002938 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Bonisch, C. et al. H2A.Z.2.2 is an alternatively spliced histone H2A.Z variant that causes severe nucleosome destabilization. Nucleic Acids Res. 40, 5951–5964 (2012).

    PubMed  PubMed Central  Google Scholar 

  79. Santoro, S. W. & Dulac, C. The activity-dependent histone variant H2BE modulates the life span of olfactory neurons. eLife 1, e00070 (2012).

    PubMed  PubMed Central  Google Scholar 

  80. Vardabasso, C. et al. Histone variants: emerging players in cancer biology. Cell. Mol. Life Sci. 71, 379–404 (2013).

    PubMed  PubMed Central  Google Scholar 

  81. Graber, M. W., Schweinfest, C. W., Reed, C. E., Papas, T. S. & Baron, P. L. Isolation of differentially expressed genes in carcinoma of the esophagus. Ann. Surg. Oncol. 3, 192–197 (1996).

    CAS  PubMed  Google Scholar 

  82. Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012). This work is the first to identify driver mutations that are specific to the histone variant H3.3 in human cancer.

    CAS  PubMed  Google Scholar 

  83. Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nature Genet. 44, 251–253 (2012).

    CAS  PubMed  Google Scholar 

  84. Khuong-Quang, D. A. et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol. 124, 439–447 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Lewis, P. W. et al. Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 340, 857–861 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Chan, K. M. et al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev. 27, 985–990 (2013). References 85 and 86 show the dominant negative effects of histone H3 mutations on the activity of PRC2 methyltransferase activity in paediatric gliomagenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Goldberg, A. D. et al. Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140, 678–691 (2010). This work provides the first genome-wide profiles of a histone variant (H3.3) in a mammalian system.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Elsaesser, S. J., Goldberg, A. D. & Allis, C. D. New functions for an old variant: no substitute for histone H3.3. Curr. Opin. Genet. Dev. 20, 110–117 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Kang, B. et al. Phosphorylation of H4 Ser47 promotes HIRA-mediated nucleosome assembly. Genes Dev. 25, 1359–1364 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Drane, P., Ouararhni, K., Depaux, A., Shuaib, M. & Hamiche, A. The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Genes Dev. 24, 1253–1265 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Lewis, P. W., Elsaesser, S. J., Noh, K. M., Stadler, S. C. & Allis, C. D. DAXX is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc. Natl Acad. Sci. USA 107, 14075–14080 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Jiao, Y. et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331, 1199–1203 (2011). This paper is the first to show that mutations in histone variant-associated chaperones are linked to human PanNETs.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Cheung, N. K. et al. Association of age at diagnosis and genetic mutations in patients with neuroblastoma. J. Am. Med. Associ. 307, 1062–1071 (2012).

    CAS  Google Scholar 

  94. Ding, L. et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481, 506–510 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Garrick, D. et al. Loss of Atrx affects trophoblast development and the pattern of X-inactivation in extraembryonic tissues. PLoS Genet. 2, e58 (2006).

    PubMed  PubMed Central  Google Scholar 

  96. Michaelson, J. S., Bader, D., Kuo, F., Kozak, C. & Leder, P. Loss of Daxx, a promiscuously interacting protein, results in extensive apoptosis in early mouse development. Genes Dev. 13, 1918–1923 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Baumann, C., Viveiros, M. M. & De La Fuente, R. Loss of maternal ATRX results in centromere instability and aneuploidy in the mammalian oocyte and pre-implantation embryo. PLoS Genet. 6, e1001137 (2010).

    PubMed  PubMed Central  Google Scholar 

  98. Wong, L. H. et al. ATRX interacts with H3.3 in maintaining telomere structural integrity in pluripotent embryonic stem cells. Genome Res. 20, 351–360 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Heaphy, C. M. et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science 333, 425 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Cao, Y. et al. Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1. Nature Commun. 4, 2810 (2013).

    Google Scholar 

  101. Behjati, S. et al. Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone. Nature Genet. 45, 1479–1482 (2013). This recent paper identifies H3.3-specific driver mutations in chondroblastoma and giant cell tumours of bone, which indicates that H3.3 mutations probably result in a large variety of human cancers.

    CAS  PubMed  Google Scholar 

  102. Broniscer, A. & Gajjar, A. Supratentorial high-grade astrocytoma and diffuse brainstem glioma: two challenges for the pediatric oncologist. Oncologist 9, 197–206 (2004).

    PubMed  Google Scholar 

  103. Barrow, J. et al. Homozygous loss of ADAM3A revealed by genome-wide analysis of pediatric high-grade glioma and diffuse intrinsic pontine gliomas. Neuro. Oncol. 13, 212–222 (2011).

    CAS  PubMed  Google Scholar 

  104. Bax, D. A. et al. A distinct spectrum of copy number aberrations in pediatric high-grade gliomas. Clin. Cancer Res. 16, 3368–3377 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Zarghooni, M. et al. Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet-derived growth factor receptor α and poly (ADP-ribose) polymerase as potential therapeutic targets. J. Clin. Oncol. 28, 1337–1344 (2010).

    CAS  PubMed  Google Scholar 

  106. Paugh, B. S. et al. Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J. Clin. Oncol. 28, 3061–3068 (2010).

    PubMed  PubMed Central  Google Scholar 

  107. Margueron, R. & Reinberg, D. The Polycomb complex PRC2 and its mark in life. Nature 469, 343–349 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Wagner, E. J. & Carpenter, P. B. Understanding the language of Lys36 methylation at histone H3. Nature Rev. Mol. Cell Biol. 13, 115–126 (2012).

    CAS  Google Scholar 

  109. Hock, H. A complex Polycomb issue: the two faces of EZH2 in cancer. Genes Dev. 26, 751–755 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Adam, S., Polo, S. E. & Almouzni, G. Transcription recovery after DNA damage requires chromatin priming by the H3.3 histone chaperone HIRA. Cell 155, 94–106 (2013). This paper is the first to demonstrate an essential role for HIRA, which is an H3.3-specific chaperone, during periods of transcriptional recovery after DNA damage.

    CAS  PubMed  Google Scholar 

  111. Black, B. E. & Cleveland, D. W. Epigenetic centromere propagation and the nature of CENP-A nucleosomes. Cell 144, 471–479 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Warburton, P. E. Chromosomal dynamics of human neocentromere formation. Chromosome Res. 12, 617–626 (2004).

    CAS  PubMed  Google Scholar 

  113. Howman, E. V. et al. Early disruption of centromeric chromatin organization in centromere protein A (Cenpa) null mice. Proc. Natl Acad. Sci. USA 97, 1148–1153 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Mishra, P. K. et al. Misregulation of Scm3p/HJURP causes chromosome instability in Saccharomyces cerevisiae and human cells. PLoS Genet. 7, e1002303 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Tomonaga, T. et al. Overexpression and mistargeting of centromere protein-A in human primary colorectal cancer. Cancer Res. 63, 3511–3516 (2003).

    CAS  PubMed  Google Scholar 

  116. Biermann, K. et al. Gene expression profiling identifies new biological markers of neoplastic germ cells. Anticancer Res. 27, 3091–3100 (2007).

    CAS  PubMed  Google Scholar 

  117. Wu, Q. et al. Expression and prognostic significance of centromere protein A in human lung adenocarcinoma. Lung Cancer 77, 407–414 (2012).

    PubMed  Google Scholar 

  118. McGovern, S. L., Qi, Y., Pusztai, L., Symmans, W. F. & Buchholz, T. A. Centromere protein-A, an essential centromere protein, is a prognostic marker for relapse in estrogen receptor-positive breast cancer. Breast Cancer Res. 14, R72 (2012).

    PubMed  PubMed Central  Google Scholar 

  119. Li, Y. M., Liu, X. H., Cao, X. Z., Wang, L. & Zhu, M. H. [Expression of centromere protein A in hepatocellular carcinoma]. Zhonghua Bing Li Xue Za Zhi 36, 175–178 (in Chinese) (2007).

    CAS  PubMed  Google Scholar 

  120. Li, Y. et al. shRNA-targeted centromere protein A inhibits hepatocellular carcinoma growth. PLoS ONE 6, e17794 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Hua, S. et al. Genomic analysis of estrogen cascade reveals histone variant H2A.Z associated with breast cancer progression. Mol. Systems Biol. 4, 188 (2008).

    Google Scholar 

  122. Dunican, D. S., McWilliam, P., Tighe, O., Parle-McDermott, A. & Croke, D. T. Gene expression differences between the microsatellite instability (MIN) and chromosomal instability (CIN) phenotypes in colorectal cancer revealed by high-density cDNA array hybridization. Oncogene 21, 3253–3257 (2002).

    CAS  PubMed  Google Scholar 

  123. Rhodes, D. R. et al. Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. Proc. Natl Acad. Sci. USA 101, 9309–9314 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Zucchi, I. et al. Gene expression profiles of epithelial cells microscopically isolated from a breast-invasive ductal carcinoma and a nodal metastasis. Proc. Natl Acad. Sci. USA 101, 18147–18152 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Xu, Y. et al. Histone H2A.Z controls a critical chromatin remodeling step required for DNA double-strand break repair. Mol. Cell 48, 723–733 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Greaves, I. K., Rangasamy, D., Ridgway, P. & Tremethick, D. J. H2A.Z contributes to the unique 3D structure of the centromere. Proc. Natl Acad. Sci. USA 104, 525–530 (2007).

    CAS  PubMed  Google Scholar 

  127. Rangasamy, D., Berven, L., Ridgway, P. & Tremethick, D. J. Pericentric heterochromatin becomes enriched with H2A.Z during early mammalian development. EMBO J. 22, 1599–1607 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Shia, W. J., Li, B. & Workman, J. L. SAS-mediated acetylation of histone H4 Lys16 is required for H2A.Z incorporation at subtelomeric regions in Saccharomyces cerevisiae. Genes Dev. 20, 2507–2512 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Rogakou, E. P., Pilch, D. R., Orr, A. H., Ivanova, V. S. & Bonner, W. M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858–5868 (1998).

    CAS  PubMed  Google Scholar 

  130. Fernandez-Capetillo, O., Lee, A., Nussenzweig, M. & Nussenzweig, A. H2AX: the histone guardian of the genome. DNA Repair 3, 959–967 (2004).

    CAS  PubMed  Google Scholar 

  131. Li, A. et al. Phosphorylation of histone H2A.X by DNA-dependent protein kinase is not affected by core histone acetylation, but it alters nucleosome stability and histone H1 binding. J. Biol. Chem. 285, 17778–17788 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Xiao, A. et al. WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity. Nature 457, 57–62 (2009).

    CAS  PubMed  Google Scholar 

  133. Zhu, F. et al. Phosphorylation of H2AX at Ser139 and a new phosphorylation site Ser16 by RSK2 decreases H2AX ubiquitination and inhibits cell transformation. Cancer Res. 71, 393–403 (2011).

    CAS  PubMed  Google Scholar 

  134. Monni, O. & Knuutila, S. 11q deletions in hematological malignancies. Leuk. Lymphoma 40, 259–266 (2001).

    CAS  PubMed  Google Scholar 

  135. Thirman, M. J. et al. Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations. New Engl. J. Med. 329, 909–914 (1993).

    CAS  PubMed  Google Scholar 

  136. Stankovic, T. et al. ATM mutations in sporadic lymphoid tumours. Leuk. Lymphoma 43, 1563–1571 (2002).

    CAS  PubMed  Google Scholar 

  137. Parikh, R. A. et al. Loss of distal 11q is associated with DNA repair deficiency and reduced sensitivity to ionizing radiation in head and neck squamous cell carcinoma. Genes Chromosomes Cancer 46, 761–775 (2007).

    CAS  Google Scholar 

  138. Srivastava, N., Gochhait, S., Gupta, P. & Bamezai, R. N. Copy number alterations of the H2AFX gene in sporadic breast cancer patients. Cancer Genet. Cytogenet. 180, 121–128 (2008).

    CAS  PubMed  Google Scholar 

  139. Sporn, J. C. & Jung, B. Differential regulation and predictive potential of macroH2A1 isoforms in colon cancer. Am. J. Pathol. 180, 2516–2526 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Sporn, J. C. et al. Histone macroH2A isoforms predict the risk of lung cancer recurrence. Oncogene 28, 3423–3428 (2009).

    CAS  PubMed  Google Scholar 

  141. Kapoor, A. et al. The histone variant macroH2A suppresses melanoma progression through regulation of CDK8. Nature 468, 1105–1109 (2010). This study shows that mH2A is a critical chromatin factor that is associated with suppression of malignant melanoma development.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Novikov, L. et al. QKI-mediated alternative splicing of the histone variant macroH2A1 regulates cancer cell proliferation. Mol. Cell. Biol. 31, 4244–4255 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Li, X. et al. The atypical histone macroH2A1.2 interacts with HER-2 protein in cancer cells. J. Biol. Chem. 287, 23171–23183 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Zhang, R. et al. Formation of macroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev. Cell 8, 19–30 (2005).

    CAS  PubMed  Google Scholar 

  145. Ratnakumar, K. et al. ATRX-mediated chromatin association of histone variant macroH2A1 regulates α-globin expression. Genes Dev. 26, 433–438 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Jullien, J., Astrand, C., Halley-Stott, R. P., Garrett, N. & Gurdon, J. B. Characterization of somatic cell nuclear reprogramming by oocytes in which a linker histone is required for pluripotency gene reactivation. Proc. Natl Acad. Sci. USA 107, 5483–5488 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Nashun, B., Akiyama, T., Suzuki, M. G. & Aoki, F. Dramatic replacement of histone variants during genome remodeling in nuclear-transferred embryos. Epigenet. 6, 1489–1497 (2011).

    CAS  Google Scholar 

  148. Chang, C. C. et al. Rapid elimination of the histone variant MacroH2A from somatic cell heterochromatin after nuclear transfer. Cell. Reprogramm. 12, 43–53 (2010).

    CAS  Google Scholar 

  149. Perez-Montero, S., Carbonell, A., Moran, T., Vaquero, A. & Azorin, F. The embryonic linker histone H1 variant of Drosophila, dBigH1, regulates zygotic genome activation. Dev. Cell 26, 578–590 (2013).

    CAS  PubMed  Google Scholar 

  150. Barrero, M. J. et al. Macrohistone variants preserve cell identity by preventing the gain of H3K4me2 during reprogramming to pluripotency. Cell Rep. 3, 1005–1011 (2013).

    CAS  PubMed  Google Scholar 

  151. Pasque, V. et al. Histone variant macroH2A marks embryonic differentiation in vivo and acts as an epigenetic barrier to induced pluripotency. J. Cell Sci. 125, 6094–6104 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Gaspar-Maia, A. et al. MacroH2A histone variants act as a barrier upon reprogramming towards pluripotency. Nature Commun. 4, 1565 (2013).

    Google Scholar 

  153. Schones, D. E. et al. Dynamic regulation of nucleosome positioning in the human genome. Cell 132, 887–898 (2008).

    CAS  PubMed  Google Scholar 

  154. Luger, K. et al. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389, 251–260 (1997).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank members of C.D.A.'s laboratory for providing critiques of the manuscript. Given the broad scope of this Review, they apologize for any relevant citations that might have been omitted. I.M., K.-M.N. and C.D.A. are partly supported by grants from the US National Institute of Mental Health (RO1 MH094698-01, P50 MH096890-01) and the Leukemia & Lymphoma Society (LLS-SCOR 7132–08). A.A.S. is supported by a Howard Hughes Medical Institute Damon Runyon Cancer Research Foundation fellowship (DRG-2185-14).

Author information

Author notes

  1. Ian Maze, Kyung-Min Noh and C. David Allis: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, 10065, New York, USA

    Ian Maze, Kyung-Min Noh, Alexey A. Soshnev & C. David Allis

Authors
  1. Ian Maze
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kyung-Min Noh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexey A. Soshnev
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. David Allis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ian Maze, Kyung-Min Noh or C. David Allis.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

Nucleosomal

Pertaining to the nucleosome, which is the basic unit of chromatin that contains ~147 bp of DNA wrapped around a histone octamer (which is composed of two copies each of histone H3, H4, H2A and H2B, or variants thereof).

Canonical histones

Archetypical histones of a given family to which all other histone proteins of that same family are compared.

Imprinted loci

Genes that are expressed from only one of the two parental copies, the choice of which is dependent on the sex of the parent from which the gene was derived.

Bivalent promoters

Regions of chromatin that have co-occurrence of histone H3 trimethylated at lysine 27 (H3K27me3) and H3K4me2 or H3K4me3 during embryonic development.

Totipotent

Pertaining to the capacity of an undifferentiated cell to develop into any type of cell.

Pronucleus

The haploid nucleus from a gamete.

Hypomorphic

Pertaining to a mutant allele that does not completely eliminate the wild-type function of a gene and that gives a less severe phenotype than a loss-of-function mutant.

Polycomb repressive complex

(PRC). An epigenetic regulator of gene expression that silences target genes by establishing a repressive chromatin state. PRC2 trimethylates histone H3 at lysine 27. This repressive histone modification is recognized by PRC1, which has ubiquitylating activity. As PRCs can maintain states of gene expression, they have key roles in cell fate maintenance and transitions during development.

Trophectoderm

The outer layer of the blastocyst-stage embryo that gives rise to the trophoblast after implantation and that will provide the bulk of the extra-embryonic lineages of the placenta.

Blastocyst

A pre-implantation embryonic stage that is characterized by the first definitive lineages. It contains a fluid-filled cavity (that is, the blastocoel), a focal cluster of cells from which the embryo develops (that is, the inner cell mass) and peripheral trophoblast cells (which form the placenta).

Inner cell mass

A cluster of undifferentiated cells in the blastocyst, which give rise to the entire fetus and to some of its extra-embryonic (that is, placental) tissues.

Gastrulation

The process by which the three primitive germ layers are formed in the early embryo; it is one of the first major differentiation events in development.

Core transcription factor

A transcription factor that controls the expression of key pluripotency-related genes. Pluripotent cells are highly responsive to levels of these transcriptional regulators.

Aneuploidy

The presence of an abnormal number of chromosomes.

Blebbing

Formation of protrusions from a membrane. Nuclear blebs are caused by localized separation of fibres from the lamin meshwork.

Bridging

Formation of abnormal connections between two nuclei, in which the nuclear membrane extends across two poorly separated or non-separated chromatin masses. Nuclear bridges are associated with failed and regressed cytokinesis.

Haploinsufficiency

A genetic condition in a diploid organism in which a single functional copy of a gene fails to generate sufficient gene product, leading to an abnormal or diseased state.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maze, I., Noh, KM., Soshnev, A. et al. Every amino acid matters: essential contributions of histone variants to mammalian development and disease. Nat Rev Genet 15, 259–271 (2014). https://doi.org/10.1038/nrg3673

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg3673

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing