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Histone variants — ancient wrap artists of the epigenome

Key Points

  • Canonical histones H2A, H2B, H3 and H4 wrap DNA to form nucleosome particles that compact the genome. Histone variants have diverse additional roles in chromosome metabolism and can differ from canonical histones in stability, DNA wrapping and specialized domains.

  • The 'universal' variants, centromeric histone variant H3 (CenH3), H3.3, H2A.Z and H2A.X, appeared before the divergence of modern eukaryotes and function in common eukaryotic cellular processes such as histone replacement, chromosome segregation, DNA repair, and transcriptional regulation. Specialized histones have arisen in some lineages to perform additional tasks.

  • Centromeric nucleosomes contain CenH3 and form the essential foundation of the kinetochore. The subunit composition of the CenH3 histone core has been the subject of lively debate and it has been found to wrap DNA in a right-handed direction, opposite to that of ordinary nucleosomes.

  • H2A.Z has a conserved role in transcription initiation that might be descended from a hypothetical ancient mode of gene regulation by histone variants found in modern trypanosomes. Dynamic cellular processes might dramatically alter the stability of H2A.Z nucleosomes and thereby facilitate transcription initiation.

  • Chromatin must be remodelled in processes such as DNA repair and sex chromosome silencing. Variants H2A.X and H3.3 have prominent roles in remodelling, with specialized sperm histones and protamines mediating sperm packaging and decondensation.

  • Lineage-specific H2A variants have diverse carboxy-terminal tails that can wrap more DNA with additional oligopeptide motifs, or less DNA with a shorter docking domain. They sometimes have non-histone domains, which in macroH2As inhibit polyADP-ribosylation and contribute to conditional gene silencing.

Abstract

Histones wrap DNA to form nucleosome particles that compact eukaryotic genomes. Variant histones have evolved crucial roles in chromosome segregation, transcriptional regulation, DNA repair, sperm packaging and other processes. 'Universal' histone variants emerged early in eukaryotic evolution and were later displaced for bulk packaging roles by the canonical histones (H2A, H2B, H3 and H4), the synthesis of which is coupled to DNA replication. Further specializations of histone variants have evolved in some lineages to perform additional tasks. Differences among histone variants in their stability, DNA wrapping, specialized domains that regulate access to DNA, and post-translational modifications, underlie the diverse functions that histones have acquired in evolution.

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Figure 1: Histone dimers, tetramers and octamers.
Figure 2: A model of H2A.Z and DNA methylation in transcription.
Figure 3: Phylogeny of H2A variants.

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References

  1. Luger, K., Mader, A. W., Richmond, R. K., Sargent, D. F. & Richmond, T. J. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389, 251–260 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Zlatanova, J., Bishop, T. C., Victor, J. M., Jackson, V. & van Holde, K. The nucleosome family: dynamic and growing. Structure 17, 160–171 (2009).

    Article  CAS  PubMed  Google Scholar 

  3. Allshire, R. C. & Karpen, G. H. Epigenetic regulation of centromeric chromatin: old dogs, new tricks? Nature Rev. Genet. 9, 923–937 (2008).

    Article  CAS  PubMed  Google Scholar 

  4. Malik, H. S. & Henikoff, S. Major evolutionary transitions in centromere complexity. Cell 138, 1067–1082 (2009).

    Article  CAS  PubMed  Google Scholar 

  5. Orsi, G. A., Couble, P. & Loppin, B. Epigenetic and replacement roles of histone variant H3.3 in reproduction and development. Int. J. Dev. Biol. 53, 231–243 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Zlatanova, J. & Thakar, A. H2A.Z: view from the top. Structure 16, 166–179 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Altaf, M., Auger, A., Covic, M. & Cote, J. Connection between histone H2A variants and chromatin remodeling complexes. Biochem. Cell Biol. 87, 35–50 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Ismail, I. H. & Hendzel, M. J. The γH2A.X: is it just a surrogate marker of double-strand breaks or much more? Environ. Mol. Mutagen. 49, 73–82 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Gonzalez-Romero, R., Mendez, J., Ausio, J. & Eirin-Lopez, J. M. Quickly evolving histones, nucleosome stability and chromatin folding: all about histone H2A.Bbd. Gene 413, 1–7 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Park, Y. J. & Luger, K. Histone chaperones in nucleosome eviction and histone exchange. Curr. Opin. Struct. Biol. 18, 282–289 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cairns, B. R. The logic of chromatin architecture and remodelling at promoters. Nature 461, 193–198 (2009).

    Article  CAS  PubMed  Google Scholar 

  13. Arents, G. & Moudrianakis, E. N. The histone fold: a ubiquitous architectural motif utilized in DNA compaction and protein dimerization. Proc. Natl Acad. Sci. USA 92, 11170–11174 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sandman, K. & Reeve, J. N. Archaeal histones and the origin of the histone fold. Curr. Opin. Microbiol. 9, 520–525 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Pereira, S. L., Grayling, R. A., Lurz, R. & Reeve, J. N. Archaeal nucleosomes. Proc. Natl. Acad. Sci. USA 94, 12633–12637 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Marc, F., Sandman, K., Lurz, R. & Reeve, J. N. Archaeal histone tetramerization determines DNA affinity and the direction of DNA supercoiling. J. Biol. Chem. 277, 30879–30886 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Fahrner, R. L., Cascio, D., Lake, J. A. & Slesarev, A. An ancestral nuclear protein assembly: crystal structure of the Methanopyrus kandleri histone. Protein Sci. 10, 2002–2007 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li, W. T., Sandman, K., Pereira, S. L. & Reeve, J. N. MJ1647, an open reading frame in the genome of the hyperthermophile Methanococcus jannaschii, encodes a very thermostable archaeal histone with a C-terminal extension. Extremophiles 4, 43–51 (2000).

    CAS  PubMed  Google Scholar 

  19. Friedrich-Jahn, U., Aigner, J., Langst, G., Reeve, J. N. & Huber, H. Nanoarchaeal origin of histone H3? J. Bacteriol. 191, 1092–1096 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Alilat, M., Sivolob, A., Revet, B. & Prunell, A. Nucleosome dynamics. Protein and DNA contributions in the chiral transition of the tetrasome, the histone (H3-H4)2 tetramer-DNA particle. J. Mol. Biol. 291, 815–841 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Hackett, J. D. et al. Insights into a dinoflagellate genome through expressed sequence tag analysis. BMC Genomics 6, 80 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Malik, H. S. & Henikoff, S. Phylogenomics of the nucleosome. Nature Struct. Biol. 10, 882–891 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Santaguida, S. & Musacchio, A. The life and miracles of kinetochores. EMBO J. 28, 2511–2531 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dawson, S. C., Sagolla, M. S. & Cande, W. Z. The CenH3 histone variant defines centromeres in Giardia intestinalis. Chromosoma 116, 175–184 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Talbert, P. B., Masuelli, R., Tyagi, A. P., Comai, L. & Henikoff, S. Centromeric localization and adaptive evolution of an Arabidopsis histone H3 variant. Plant Cell 14, 1053–1066 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Earnshaw, W. C. & Rothfield, N. Identification of a family of human centromere proteins using autoimmune sera from patients with scleroderma. Chromosoma 91, 313–321 (1985).

    Article  CAS  PubMed  Google Scholar 

  27. Malik, H. S., Vermaak, D. & Henikoff, S. Recurrent evolution of DNA-binding motifs in the Drosophila centromeric histone. Proc. Natl Acad. Sci. USA. 99, 1449–1454 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Churchill, M. E. & Suzuki, M. 'SPKK' motifs prefer to bind to DNA at A/T-rich sites. EMBO J. 8, 4189–4195 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wieland, G., Orthaus, S., Ohndorf, S., Diekmann, S. & Hemmerich, P. Functional complementation of human centromere protein A (CENP-A) by Cse4p from Saccharomyces cerevisiae. Mol. Cell. Biol. 24, 6620–6630 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Dalal, Y., Wang, H., Lindsay, S. & Henikoff, S. Tetrameric structure of centromeric nucleosomes in interphase Drosophila cells. PLoS Biol. 5, e218 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Furuyama, T. & Henikoff, S. Centromeric nucleosomes induce positive DNA supercoils. Cell 138, 104–113 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mizuguchi, G., Xiao, H., Wisniewski, J., Smith, M. M. & Wu, C. Nonhistone Scm3 and histones CenH3-H4 assemble the core of centromere-specific nucleosomes. Cell 129, 1153–1164 (2007).

    Article  CAS  PubMed  Google Scholar 

  33. Camahort, R. et al. Cse4 is part of an octameric nucleosome in budding yeast. Mol. Cell 35, 794–805 (2009). Together with references 30 and 32, this paper proposes mutually exclusive models for the CenH3 histone core; the correct model needs to accommodate the result of reference 31, which shows that CenH3 DNA wraps around the core in a right-handed direction.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Westermann, S. et al. Architecture of the budding yeast kinetochore reveals a conserved molecular core. J. Cell Biol. 163, 215–222 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Conde E Silva, N. et al. CENP-A-containing nucleosomes: easier disassembly versus exclusive centromeric localization. J. Mol. Biol. 370, 555–573 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Dalal, Y., Furuyama, T., Vermaak, D. & Henikoff, S. Structure, dynamics, and evolution of centromeric nucleosomes. Proc. Natl Acad. Sci. USA 104, 15974–15981 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Cui, B., Liu, Y. & Gorovsky, M. A. Deposition and function of histone H3 variants in Tetrahymena thermophila. Mol. Cell. Biol. 26, 7719–7730 (2006). Mutational analysis of canonical histone H3 and H3.3 shows that H3 is not essential in ciliate development, and H3.3 is not essential for transcription but is required in germline micronuclei.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ahmad, K. & Henikoff, S. The histone variant H3.3 marks active chromatin by replication-independent nucleosome assembly. Mol. Cell 9, 1191–1200 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Tagami, H., Ray-Gallet, D., Almouzni, G. & Nakatani, Y. Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis. Cell 116, 51–61 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Polo, S. E., Roche, D. & Almouzni, G. New histone incorporation marks sites of UV repair in human cells. Cell 127, 481–493 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Mousson, F., Ochsenbein, F. & Mann, C. The histone chaperone Asf1 at the crossroads of chromatin and DNA checkpoint pathways. Chromosoma 116, 79–93 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Henikoff, S. Nucleosome destabilization in the epigenetic regulation of gene expression. Nature Rev. Genet. 9, 15–26 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Schwartz, B. E. & Ahmad, K. Transcriptional activation triggers deposition and removal of the histone variant H3.3. Genes Dev. 19, 804–814 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sutcliffe, E. L. et al. Dynamic histone variant exchange accompanies gene induction in T cells. Mol. Cell. Biol. 29, 1972–1986 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Loyola, A., Bonaldi, T., Roche, D., Imhof, A. & Almouzni, G. PTMs on H3 variants before chromatin assembly potentiate their final epigenetic state. Mol. Cell 24, 309–316 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Ng, R. K. & Gurdon, J. B. Epigenetic memory of an active gene state depends on histone H3.3 incorporation into chromatin in the absence of transcription. Nature Cell Biol. 10, 102–109 (2008). Using a Xenopus laevis nuclear transplantation assay, the authors show that epigenetic memory of a gene expression state is retained through 12 rounds of cell division without transcription and depends on the presence of wild-type H3.3 but not H3.

    Article  CAS  PubMed  Google Scholar 

  48. 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).

    Article  CAS  PubMed  Google Scholar 

  49. Ooi, S. L., Priess, J. R. & Henikoff, S. Histone H3.3 variant dynamics in the germline of Caenorhabditis elegans. PLoS Genet. 2, e97 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jin, C. & Felsenfeld, G. Nucleosome stability mediated by histone variants H3.3 and H2A. Z. Genes Dev. 21, 1519–1529 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hodl, M. & Basler, K. Transcription in the absence of histone H3.3. Curr. Biol. 19, 1221–1226 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. 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). References 51 and 52 show that H3.3 is dispensible for normal Drosophila development but is essential in the germ line, and reference 52 shows that the germline function does not require methylation of H3.3K4 or phosphorylation of Ser31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Schulmeister, A., Schmid, M. & Thompson, E. M. Phosphorylation of the histone H3.3 variant in mitosis and meiosis of the urochordate Oikopleura dioica. Chromosome Res. 15, 189–201 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Wong, L. H. et al. Histone H3.3 incorporation provides a unique and functionally essential telomeric chromatin in embryonic stem cells. Genome Res. 19, 404–414 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Adam, M., Robert, F., Larochelle, M. & Gaudreau, L. H2A.Z is required for global chromatin integrity and for recruitment of RNA polymerase II under specific conditions. Mol. Cell. Biol. 21, 6270–6279 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hardy, S. et al. The euchromatic and heterochromatic landscapes are shaped by antagonizing effects of transcription on H2A.Z deposition. PLoS Genet. 5, e1000687 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zofall, M. et al. Histone H2A.Z cooperates with RNAi and heterochromatin factors to suppress antisense RNAs. Nature 461, 419–422 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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). Reports a striking correlation between H2A.Z and Polycomb group protein locations in mouse embryonic stem cells but not in their differentiated descendants, suggesting that H2A.Z plays a key role in maintaining pluripotency.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zilberman, D., Coleman-Derr, D., Ballinger, T. & Henikoff, S. Histone H2A.Z and DNA methylation are mutually antagonistic chromatin marks. Nature 456, 125–129 (2008). In A. thaliana , H2A.Z and DNA methylation are found to be quantitatively anti-correlated, and mutants in either one result in opposite changes in the other.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Thakar, A. et al. H2A.Z and H3.3 histone variants affect nucleosome structure: biochemical and biophysical studies. Biochemistry 48, 10852–10857 (2009). In contrast to the in vivo results of reference 68, these authors were unable to detect significant instability of H2A.Z and H3.3 nucleosomes in vitro.

    Article  CAS  PubMed  Google Scholar 

  61. Goldman, J. A., Garlick, J. D. & Kingston, R. E. Chromatin remodeling by imitation switch (ISWI) class ATP-dependent remodelers is stimulated by histone variant H2A. Z. J. Biol. Chem. 285, 4645–4651 (2009). This paper shows that H2A.Z nucleosomes are preferentially associated with nucleosome remodellers, with an enhanced activity of ISWI family remodellers that is dependent on the H2A.Z extended acidic patch.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  64. March-Diaz, R. et al. Histone H2A.Z and homologues of components of the SWR1 complex are required to control immunity in Arabidopsis. Plant J. 53, 475–487 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Ishibashi, T. et al. Acetylation of vertebrate H2A.Z and its effect on the structure of the nucleosome. Biochemistry 48, 5007–5017 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Viens, A. et al. Analysis of human histone H2AZ deposition in vivo argues against its direct role in epigenetic templating mechanisms. Mol. Cell. Biol. 26, 5325–5335 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhang, H., Roberts, D. N. & Cairns, B. R. Genome-wide dynamics of Htz1, a histone H2A variant that poises repressed/basal promoters for activation through histone loss. Cell 123, 219–231 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 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). Reports that nucleosomes containing both H3.3 and H2A.Z occupy promoters and insulator elements in vivo and are highly unstable.

    Article  CAS  PubMed  Google Scholar 

  69. Hartley, P. D. & Madhani, H. D. Mechanisms that specify promoter nucleosome location and identity. Cell 137, 445–458 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Mavrich, T. N. et al. Nucleosome organization in the Drosophila genome. Nature 453, 358–362 (2008). The authors mapped a large collection of Drosophila H2Av (H2A.Z) nucleosomes and found that where RNA polymerase II is paused just downstream of the transcriptional start site, the +1 H2A.Z nucleosome is positioned another 10 bp (1 rotational turn) further downstream, suggesting a role for H2A.Z in pausing polymerase.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Jiang, C. & Pugh, B. F. Nucleosome positioning and gene regulation: advances through genomics. Nature Rev. Genet. 10, 161–172 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Gevry, N., Chan, H. M., Laflamme, L., Livingston, D. M. & Gaudreau, L. p21 transcription is regulated by differential localization of histone H2A. Z. Genes Dev. 21, 1869–1881 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gevry, N. et al. Histone H2A.Z is essential for estrogen receptor signaling. Genes Dev. 23, 1522–1533 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Choi, J., Heo, K. & An, W. Cooperative action of TIP48 and TIP49 in H2A.Z exchange catalyzed by acetylation of nucleosomal H2A. Nucleic Acids Res. 37, 5993–6007 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Fan, J. Y., Gordon, F., Luger, K., Hansen, J. C. & Tremethick, D. J. The essential histone variant H2A.Z regulates the equilibrium between different chromatin conformational states. Nature Struct. Biol. 9, 172–176 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Deal, R. B., Topp, C. N., McKinney, E. C. & Meagher, R. B. Repression of flowering in Arabidopsis requires activation of FLOWERING LOCUS C expression by the histone variant H2A. Z. Plant Cell 19, 74–83 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ball, M. P. et al. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nature Biotechnol. 27, 361–368 (2009).

    Article  CAS  Google Scholar 

  78. Fan, J. Y., Rangasamy, D., Luger, K. & Tremethick, D. J. H2A.Z alters the nucleosome surface to promote HP1α-mediated chromatin fiber folding. Mol. Cell 16, 655–661 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Swaminathan, J., Baxter, E. M. & Corces, V. G. The role of histone H2Av variant replacement and histone H4 acetylation in the establishment of Drosophila heterochromatin. Genes Dev. 19, 65–76 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hanai, K., Furuhashi, H., Yamamoto, T., Akasaka, K. & Hirose, S. RSF governs silent chromatin formation via histone H2Av replacement. PLoS Genet. 4, e1000011 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. van Attikum, H. & Gasser, S. M. Crosstalk between histone modifications during the DNA damage response. Trends Cell Biol. 19, 207–217 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Shechter, D. et al. A distinct H2A.X isoform is enriched in Xenopus laevis eggs and early embryos and is phosphorylated in the absence of a checkpoint. Proc. Natl Acad. Sci. USA 106, 749–754 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  84. 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).

    Article  CAS  PubMed  Google Scholar 

  85. Turner, J. M. et al. Silencing of unsynapsed meiotic chromosomes in the mouse. Nature Genet. 37, 41–47 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Van Doninck, K. et al. Phylogenomics of unusual histone H2A variants in Bdelloid rotifers. PLoS Genet. 5, e1000401 (2009). Shows that bdelloid rotifers, which periodically undergo severe dessication resulting in massive DNA breaks, have replaced H2A.X, which recruits DNA repair machinery in other eukaryotes, with novel H2A variants that might have evolved to facilitate DNA repair under dessicating conditions.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Marzluff, W. F., Gongidi, P., Woods, K. R., Jin, J. & Maltais, L. J. The human and mouse replication-dependent histone genes. Genomics 80, 487–498 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Marzluff, W. F., Sakallah, S. & Kelkar, H. The sea urchin histone gene complement. Dev. Biol. 300, 308–320 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Siegel, T. N. et al. Four histone variants mark the boundaries of polycistronic transcription units in Trypanosoma brucei. Genes Dev. 23, 1063–1076 (2009). Reports that trypanosomes have two versions of each of the four core histones, which form unique combinations at transcription initiation sites and termination sites. This suggests the existence of an ancestral mode of gene regulation based on histone variants and an ancient function for H2A.Z in marking promoters.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Bernhard, D. & Schlegel, M. Evolution of histone H4 and H3 genes in different ciliate lineages. J. Mol. Evol. 46, 344–354 (1998).

    Article  CAS  PubMed  Google Scholar 

  91. Katz, L. A., Bornstein, J. G., Lasek-Nesselquist, E. & Muse, S. V. Dramatic diversity of ciliate histone H4 genes revealed by comparisons of patterns of substitutions and paralog divergences among eukaryotes. Mol. Biol. Evol. 21, 555–562 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Gladyshev, E. & Meselson, M. Extreme resistance of bdelloid rotifers to ionizing radiation. Proc. Natl Acad. Sci. USA 105, 5139–5144 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Pehrson, J. R. & Fuji, R. N. Evolutionary conservation of histone macroH2A subtypes and domains. Nucleic Acids Res. 26, 2837–2842 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chadwick, B. P. & Willard, H. F. Histone H2A variants and the inactive X chromosome: identification of a second macroH2A variant. Hum. Mol. Genet. 10, 1101–1113 (2001).

    Article  CAS  PubMed  Google Scholar 

  95. Costanzi, C. & Pehrson, J. R. MACROH2A2, a new member of the MARCOH2A core histone family. J. Biol. Chem. 276, 21776–21784 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Abbott, D. W., Chadwick, B. P., Thambirajah, A. A. & Ausio, J. Beyond the Xi: macroH2A chromatin distribution and post-translational modification in an avian system. J. Biol. Chem. 280, 16437–16445 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Doyen, C. M. et al. Mechanism of polymerase II transcription repression by the histone variant macroH2A. Mol. Cell. Biol. 26, 1156–1164 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Chakravarthy, S. & Luger, K. The histone variant macro-H2A preferentially forms “hybrid nucleosomes”. J. Biol. Chem. 281, 25522–25531 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Nusinow, D. A. et al. Poly(ADP-ribose) polymerase 1 is inhibited by a histone H2A variant, MacroH2A, and contributes to silencing of the inactive X chromosome. J. Biol. Chem. 282, 12851–12859 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Timinszky, G. et al. A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation. Nature Struct. Mol. Biol. 16, 923–929 (2009).

    Article  CAS  Google Scholar 

  101. Ouararhni, K. et al. The histone variant mH2A1.1 interferes with transcription by down-regulating PARP-1 enzymatic activity. Genes Dev. 20, 3324–3336 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Buschbeck, M. et al. The histone variant macroH2A is an epigenetic regulator of key developmental genes. Nature Struct. Mol. Biol. (2009). This paper shows that mH2A serves as a repressive mark on autosomes, overlapping with Polycomb repressor complex 2 sites and contributing to regulation of homeobox genes during neuronal differentiation.

  103. Eirin-Lopez, J. M., Ishibashi, T. & Ausio, J. H2A.Bbd: a quickly evolving hypervariable mammalian histone that destabilizes nucleosomes in an acetylation-independent way. FASEB J. 22, 316–326 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Chadwick, B. P. & Willard, H. F. A novel chromatin protein, distantly related to histone H2A, is largely excluded from the inactive X chromosome. J. Cell Biol. 152, 375–384 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Gautier, T. et al. Histone variant H2ABbd confers lower stability to the nucleosome. EMBO Rep. 5, 715–720 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Okuwaki, M., Kato, K., Shimahara, H., Tate, S. & Nagata, K. Assembly and disassembly of nucleosome core particles containing histone variants by human nucleosome assembly protein I. Mol. Cell. Biol. 25, 10639–10651 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zhou, J., Fan, J. Y., Rangasamy, D. & Tremethick, D. J. The nucleosome surface regulates chromatin compaction and couples it with transcriptional repression. Nature Struct. Mol. Biol. 14, 1070–1076 (2007).

    Article  CAS  Google Scholar 

  108. Yi, H. et al. Constitutive expression exposes functional redundancy between the Arabidopsis histone H2A gene HTA1 and other H2A gene family members. Plant Cell 18, 1575–1589 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bergmuller, E., Gehrig, P. M. & Gruissem, W. Characterization of post-translational modifications of histone H2B-variants isolated from Arabidopsis thaliana. J. Proteome Res. 6, 3655–3668 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Lindsey, G. G., Orgeig, S., Thompson, P., Davies, N. & Maeder, D. L. Extended C-terminal tail of wheat histone H2A interacts with DNA of the “linker” region. J. Mol. Biol. 218, 805–813 (1991).

    Article  CAS  PubMed  Google Scholar 

  111. Green, G. R. Phosphorylation of histone variant regions in chromatin: unlocking the linker? Biochem. Cell Biol. 79, 275–287 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Eirin-Lopez, J. M. & Ausio, J. Origin and evolution of chromosomal sperm proteins. Bioessays 31, 1062–1070 (2009).

    Article  CAS  PubMed  Google Scholar 

  113. Hammoud, S. S. et al. Distinctive chromatin in human sperm packages genes for embryo development. Nature 460, 473–478 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Palmer, D. K., O'Day, K. & Margolis, R. L. The centromere specific histone CENP-A is selectively retained in discrete foci in mammalian sperm nuclei. Chromosoma 100, 32–36 (1990).

    Article  CAS  PubMed  Google Scholar 

  115. Gatewood, J. M., Cook, G. R., Balhorn, R., Schmid, C. W. & Bradbury, E. M. Isolation of four core histones from human sperm chromatin representing a minor subset of somatic histones. J. Biol. Chem. 265, 20662–20666 (1990).

    CAS  PubMed  Google Scholar 

  116. van der Heijden, G. W. et al. Sperm-derived histones contribute to zygotic chromatin in humans. BMC Dev. Biol. 8, 34 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Ueda, K. et al. Unusual core histones specifically expressed in male gametic cells of Lilium longiflorum. Chromosoma 108, 491–500 (2000).

    Article  CAS  PubMed  Google Scholar 

  118. Ingouff, M., Hamamura, Y., Gourgues, M., Higashiyama, T. & Berger, F. Distinct dynamics of HISTONE3 variants between the two fertilization products in plants. Curr. Biol. 17, 1032–1037 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Talbert, P. B. & Henikoff, S. Chromatin-based transcriptional punctuation. Genes Dev. 23, 1037–1041 (2009).

    Article  CAS  PubMed  Google Scholar 

  120. Aggarwal, B. D. & Calvi, B. R. Chromatin regulates origin activity in Drosophila follicle cells. Nature 430, 372–376 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Miotto, B. & Struhl, K. HBO1 histone acetylase is a coactivator of the replication licensing factor Cdt1. Genes Dev. 22, 2633–2638 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ren, Q. & Gorovsky, M. A. Histone H2A.Z acetylation modulates an essential charge patch. Mol. Cell 7, 1329–1335 (2001).

    Article  CAS  PubMed  Google Scholar 

  123. Millar, C. B., Xu, F., Zhang, K. & Grunstein, M. Acetylation of H2AZ Lys 14 is associated with genome-wide gene activity in yeast. Genes Dev. 20, 711–722 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Tanabe, M. et al. Activation of facultatively silenced Drosophila loci associates with increased acetylation of histone H2AvD. Genes Cells 13, 1279–1288 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Wan, Y. et al. Role of the histone variant H2A.Z/Htz1p in TBP recruitment, chromatin dynamics, and regulated expression of oleate-responsive genes. Mol. Cell. Biol. 29, 2346–2358 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. de Napoles, M. et al. Polycomb group proteins Ring1A/B link ubiquitylation of histone H2A to heritable gene silencing and X inactivation. Dev. Cell. 7, 663–676 (2004).

    Article  CAS  PubMed  Google Scholar 

  127. Sarcinella, E., Zuzarte, P. C., Lau, P. N., Draker, R. & Cheung, P. Monoubiquitylation of H2A.Z distinguishes its association with euchromatin or facultative heterochromatin. Mol. Cell. Biol. 27, 6457–6468 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Stock, J. K. et al. Ring1-mediated ubiquitination of H2A restrains poised RNA polymerase II at bivalent genes in mouse ES cells. Nature Cell Biol. 9, 1428–1435 (2007).

    Article  CAS  PubMed  Google Scholar 

  129. Wang, H. et al. Role of histone H2A ubiquitination in Polycomb silencing. Nature 431, 873–878 (2004).

    Article  CAS  PubMed  Google Scholar 

  130. Sogin, M. L. & Silberman, J. D. Evolution of the protists and protistan parasites from the perspective of molecular systematics. Int. J. Parasitol. 28, 11–20 (1998).

    Article  CAS  PubMed  Google Scholar 

  131. Clayton, C. E. Life without transcriptional control? From fly to man and back again. EMBO J. 21, 1881–1888 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Martinez-Calvillo, S., Nguyen, D., Stuart, K. & Myler, P. J. Transcription initiation and termination on Leishmania major chromosome 3. Eukaryot. Cell. 3, 506–517 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Vanacova, S., Liston, D. R., Tachezy, J. & Johnson, P. J. Molecular biology of the amitochondriate parasites, Giardia intestinalis, Entamoeba histolytica and Trichomonas vaginalis. Int. J. Parasitol. 33, 235–255 (2003).

    Article  CAS  PubMed  Google Scholar 

  134. Lowell, J. E. & Cross, G. A. A variant histone H3 is enriched at telomeres in Trypanosoma brucei. J. Cell. Sci. 117, 5937–5947 (2004).

    Article  CAS  PubMed  Google Scholar 

  135. Ghosh, S. & Klobutcher, L. A. A development-specific histone H3 localizes to the developing macronucleus of Euplotes. Genesis 26, 179–188 (2000).

    Article  CAS  PubMed  Google Scholar 

  136. Cui, B. & Gorovsky, M. A. Centromeric histone H3 is essential for vegetative cell division and for DNA elimination during conjugation in Tetrahymena thermophila. Mol. Cell. Biol. 26, 4499–4510 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Zeitlin, S. G. et al. Double-strand DNA breaks recruit the centromeric histone CENP-A. Proc. Natl Acad. Sci. USA 106, 15762–15767 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Cervantes, M. D., Xi, X., Vermaak, D., Yao, M. C. & Malik, H. S. The CNA1 histone of the ciliate Tetrahymena thermophila is essential for chromosome segregation in the germline micronucleus. Mol. Biol. Cell 17, 485–497 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Iribarren, C., Morin, V., Puchi, M. & Imschenetzky, M. Sperm nucleosomes disassembly is a requirement for histones proteolysis during male pronucleus formation. J. Cell. Biochem. 103, 447–455 (2008).

    Article  CAS  PubMed  Google Scholar 

  140. Govin, J. et al. Pericentric heterochromatin reprogramming by new histone variants during mouse spermiogenesis. J. Cell Biol. 176, 283–294 (2007). Describes new H2A variants enriched in pericentric heterochromatin in spermatids that form sub-nucleosomal chromatin particles lacking H3 and H4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Tachiwana, H., Osakabe, A., Kimura, H. & Kurumizaka, H. Nucleosome formation with the testis-specific histone H3 variant, H3t, by human nucleosome assembly proteins in vitro. Nucleic Acids Res. 36, 2208–2218 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  143. Churikov, D. et al. Novel human testis-specific histone H2B encoded by the interrupted gene on the X chromosome. Genomics 84, 745–756 (2004).

    Article  CAS  PubMed  Google Scholar 

  144. Boulard, M. et al. The NH2 tail of the novel histone variant H2BFWT exhibits properties distinct from conventional H2B with respect to the assembly of mitotic chromosomes. Mol. Cell. Biol. 26, 1518–1526 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Aul, R. B. & Oko, R. J. The major subacrosomal occupant of bull spermatozoa is a novel histone H2B variant associated with the forming acrosome during spermiogenesis. Dev. Biol. 242, 376–387 (2002).

    Article  CAS  PubMed  Google Scholar 

  146. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Gaucher, J. et al. From meiosis to postmeiotic events: the secrets of histone disappearance. FEBS J. 277, 509–604 (2009).

    Google Scholar 

  148. Huson, D. H. et al. Dendroscope: an interactive viewer for large phylogenetic trees. BMC Bioinformatics 8, 460 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank our colleagues for stimulating discussions and anonymous reviewers for their helpful comments. Our work has been funded by the Howard Hughes Medical Institute.

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Glossary

Histone chaperone

An escort protein that performs a transfer reaction on a histone, such as deposition onto DNA, eviction from DNA, transfer to another chaperone or enzyme, or storage for later use.

Supercoil

A contortion in DNA that occurs as a consequence to over- or under-twisting of the DNA helix. Supercoils can be introduced during DNA packaging and DNA–RNA synthesis. Topoisomerases sense supercoiling and can either generate or dissipate it by changing DNA topology.

Centromere

The region of a chromosome that is attached to the spindle during nuclear division.

Kinetochore

A large multiprotein complex that assembles onto the centromere of the chromosome and links it to the microtubules of the mitotic spindle. The kinetochore is also a signalling centre for many of the proteins that control the progression of mitosis.

Epigenetic memory

An effect on gene expression or function that is not a result of DNA sequence changes and is heritable through cell division.

Nuclease-hypersensitive site

A chromosomal site that shows increased sensitivity to nucleases such as DNase I and that are correlated to regions of reduced nucleosome density and gene regulatory sites.

Heterochromatin

A highly condensed form of chromatin with very low transcriptional activity. It occurs at defined sites, such as around centromeres or telomeres. Typically it is composed of repetitive sequences and transposons, with few genes present.

Homeobox gene

One of a family of genes that encode homeodomain-containing transcription factors, which are involved in the patterning of the body during development.

Protamine

A small, highly basic protein that tightly packages sperm DNA, replacing histones completely or to varying degrees in many animals.

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Talbert, P., Henikoff, S. Histone variants — ancient wrap artists of the epigenome. Nat Rev Mol Cell Biol 11, 264–275 (2010). https://doi.org/10.1038/nrm2861

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