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:

Histone variants on the move: substrates for chromatin dynamics

Nature Reviews Molecular Cell Biology volume 18, pages 115–126 (2017)Cite this article

Subjects

Key Points

  • Histone variants replace canonical histones to carry out diverse roles in replication, transcription and heterochromatin formation, all of which are mediated by the activity of chaperones, chromatin remodellers and histone-modifying enzymes.

  • Some chaperones have evolved to distinguish between histone variants and canonical histones and direct them into specialized assembly pathways, whereas other chaperones process variants and canonical histones similarly.

  • The MCM2 subunit of the replication helicase does not distinguish between canonical H3 and its variants, and may pass different H3 variants as well as post-translationally modified H3 from the front to the back of the replication fork. By contrast, new nucleosomes comprising canonical histones are deposited behind the fork by the chaperone chromatin assembly factor 1 (CAF1), which excludes H3 variants.

  • H2A.Z has a conserved role in transcription initiation, which nevertheless varies between organisms and contexts. H2A.Z is found flanking promoters and in some enhancers and can recruit RNA polymerase II, but is then evicted by the transcription machinery.

  • Other H2A variants — H2A.B and macroH2A — can occupy specific promoters in specific cell types. H2A.B, which wraps only ∼120 bp of DNA, appears to facilitate transcription, whereas macroH2a may reinforce active or repressed expression states.

  • H3.3 has high turnover rates at regulatory elements such as enhancers. HIRA deposits H3.3 in gene bodies to replace nucleosomes evicted during transcription, whereas ATRX–DAXX (alpha thalassemia mental retardation syndrome X-linked–death domain associated protein) complex deposits H3.3 into heterochromatin, where it is necessary for maintaining H3 Lys9 trimethylation and preventing transcription of silenced repetitive elements.

  • H2A.Z is necessary for the maintenance of heterochromatin in animals, possibly because chaperones for canonical H2A are not active in heterochromatin outside of S phase. In plants, H2A.W, which wraps 162 bp of DNA, is necessary for heterochromatin condensation.

Abstract

Most histones are assembled into nucleosomes behind the replication fork to package newly synthesized DNA. By contrast, histone variants, which are encoded by separate genes, are typically incorporated throughout the cell cycle. Histone variants can profoundly change chromatin properties, which in turn affect DNA replication and repair, transcription, and chromosome packaging and segregation. Recent advances in the study of histone replacement have elucidated the dynamic processes by which particular histone variants become substrates of histone chaperones, ATP-dependent chromatin remodellers and histone-modifying enzymes. Here, we review histone variant dynamics and the effects of replacing DNA synthesis-coupled histones with their replication-independent variants on the chromatin landscape.

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: Histone variant dynamics during replication in animals.
Figure 2: Histone variant dynamics during transcription.
Figure 3: H3.3 in heterochromatin maintenance.

Similar content being viewed by others

References

  1. Macvanin, M. & Adhya, S. Architectural organization in E. coli nucleoid. Biochim. Biophys. Acta 1819, 830–835 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Peeters, E., Driessen, R. P., Werner, F. & Dame, R. T. The interplay between nucleoid organization and transcription in archaeal genomes. Nat. Rev. Microbiol. 13, 333–341 (2015).

    CAS  PubMed  Google Scholar 

  3. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Song, F. et al. Cryo-EM study of the chromatin fiber reveals a double helix twisted by tetranucleosomal units. Science 344, 376–380 (2014).

    CAS  PubMed  Google Scholar 

  6. Kurat, C. F. et al. Regulation of histone gene transcription in yeast. Cell. Mol. Life Sci. 71, 599–613 (2014).

    CAS  PubMed  Google Scholar 

  7. Marzluff, W. F. Metazoan replication-dependent histone mRNAs: a distinct set of RNA polymerase II transcripts. Curr. Opin. Cell Biol. 17, 274–280 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  9. Waterborg, J. H. & Robertson, A. J. Common features of analogous replacement histone H3 genes in animals and plants. J. Mol. Evol. 43, 194–206 (1996).

    CAS  PubMed  Google Scholar 

  10. Steiner, F. A. & Henikoff, S. Diversity in the organization of centromeric chromatin. Curr. Opin. Genet. Dev. 31, 28–35 (2015).

    CAS  PubMed  Google Scholar 

  11. McKinley, K. L. & Cheeseman, I. M. The molecular basis for centromere identity and function. Nat. Rev. Mol. Cell Biol. 17, 16–29 (2016).

    CAS  PubMed  Google Scholar 

  12. Ray-Gallet, D. et al. Dynamics of histone H3 deposition in vivo reveal a nucleosome gap-filling mechanism for H3.3 to maintain chromatin integrity. Mol. Cell 44, 928–941 (2011).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Schneiderman, J. I., Orsi, G. A., Hughes, K. T., Loppin, B. & Ahmad, K. Nucleosome-depleted chromatin gaps recruit assembly factors for the H3.3 histone variant. Proc. Natl Acad. Sci. USA 109, 19721–19726 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Soboleva, T. A. et al. A unique H2A histone variant occupies the transcriptional start site of active genes. Nat. Struct. Mol. Biol. 19, 25–30 (2011).

    PubMed  Google Scholar 

  17. 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 

  18. Yelagandula, R. et al. The histone variant H2A.W defines heterochromatin and promotes chromatin condensation in Arabidopsis. Cell 158, 98–109 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Gurard-Levin, Z. A., Quivy, J. P. & Almouzni, G. Histone chaperones: assisting histone traffic and nucleosome dynamics. Annu. Rev. Biochem. 83, 487–517 (2014).

    CAS  PubMed  Google Scholar 

  20. McKittrick, E., Gafken, P. R., Ahmad, K. & Henikoff, S. Histone H3.3 is enriched in covalent modifications associated with active chromatin. Proc. Natl Acad. Sci. USA 101, 1525–1530 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Chang, F. T. et al. CHK1-driven histone H3.3 serine 31 phosphorylation is important for chromatin maintenance and cell survival in human ALT cancer cells. Nucleic Acids Res. 43, 2603–2614 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ismail, I. H. & Hendzel, M. J. The γ-H2A.X: is it just a surrogate marker of double-strand breaks or much more? Environ. Mol. Mutagen. 49, 73–82 (2008).

    CAS  PubMed  Google Scholar 

  23. 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 

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

    CAS  PubMed  Google Scholar 

  25. Turinetto, V. & Giachino, C. Histone variants as emerging regulators of embryonic stem cell identity. Epigenetics 10, 563–573 (2015).

    PubMed  PubMed Central  Google Scholar 

  26. Gaume, X. & Torres-Padilla, M. E. Regulation of reprogramming and cellular plasticity through histone exchange and histone variant incorporation. Cold Spring Harb. Symp. Quant. Biol. 80, 165–175 (2015).

    PubMed  Google Scholar 

  27. Gursoy-Yuzugullu, O., House, N. & Price, B. D. Patching broken DNA: nucleosome dynamics and the repair of DNA breaks. J. Mol. Biol. 428, 1846–1860 (2015).

    PubMed  PubMed Central  Google Scholar 

  28. Talbert, P. B. & Henikoff, S. Environmental responses mediated by histone variants. Trends Cell Biol. 24, 642–650 (2014).

    CAS  PubMed  Google Scholar 

  29. Laskey, R. A., Honda, B. M., Mills, A. D. & Finch, J. T. Nucleosomes are assembled by an acidic protein which binds histones and transfers them to DNA. Nature 275, 416–420 (1978).

    CAS  PubMed  Google Scholar 

  30. Tripathi, A. K., Singh, K., Pareek, A. & Singla-Pareek, S. L. Histone chaperones in Arabidopsis and rice: genome-wide identification, phylogeny, architecture and transcriptional regulation. BMC Plant Biol. 15, 42 (2015).

    PubMed  PubMed Central  Google Scholar 

  31. Alvarez, F. et al. Sequential establishment of marks on soluble histones H3 and H4. J. Biol. Chem. 286, 17714–17721 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Campos, E. I. et al. The program for processing newly synthesized histones H3.1 and H4. Nat. Struct. Mol. Biol. 17, 1343–1351 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 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).

    CAS  PubMed  Google Scholar 

  34. Green, E. M. et al. Replication-independent histone deposition by the HIR complex and Asf1. Curr. Biol. 15, 2044–2049 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Liu, W. H., Roemer, S. C., Port, A. M. & Churchill, M. E. CAF-1-induced oligomerization of histones H3/H4 and mutually exclusive interactions with Asf1 guide H3/H4 transitions among histone chaperones and DNA. Nucleic Acids Res. 40, 11229–11239 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Waterborg, J. H. Evolution of histone H3: emergence of variants and conservation of post-translational modification sites. Biochem. Cell Biol. 90, 79–95 (2012).

    CAS  PubMed  Google Scholar 

  37. Latreille, D., Bluy, L., Benkirane, M. & Kiernan, R. E. Identification of histone 3 variant 2 interacting factors. Nucleic Acids Res. 42, 3542–3550 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Abascal, F. et al. Subfunctionalization via adaptive evolution influenced by genomic context: the case of histone chaperones ASF1a and ASF1b. Mol. Biol. Evol. 30, 1853–1866 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  40. Elsasser, S. J. et al. DAXX envelops a histone H3.3–H4 dimer for H3.3-specific recognition. Nature 491, 560–565 (2012). Recognition of Gly90 found in H3.3 but not H3.1 or H3.2 by the histone chaperone DAXX distinguishes the otherwise almost identical variants.

    PubMed  PubMed Central  Google Scholar 

  41. Lacoste, N. et al. Mislocalization of the centromeric histone variant CenH3/CENP-A in human cells depends on the chaperone DAXX. Mol. Cell 53, 631–644 (2014).

    CAS  PubMed  Google Scholar 

  42. Athwal, R. K. et al. CENP-A nucleosomes localize to transcription factor hotspots and subtelomeric sites in human cancer cells. Epigenetics Chromatin 8, 2 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 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 

  44. 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 

  45. Goldberg, A. D. et al. Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell 140, 678–691 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Delbarre, E., Ivanauskiene, K., Kuntziger, T. & Collas, P. DAXX-dependent supply of soluble (H3.3–H4) dimers to PML bodies pending deposition into chromatin. Genome Res. 23, 440–451 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Schlesinger, M. B. & Formosa, T. POB3 is required for both transcription and replication in the yeast Saccharomyces cerevisiae. Genetics 155, 1593–1606 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Belotserkovskaya, R. et al. FACT facilitates transcription-dependent nucleosome alteration. Science 301, 1090–1093 (2003).

    CAS  PubMed  Google Scholar 

  49. Mason, P. B. & Struhl, K. The FACT complex travels with elongating RNA polymerase II and is important for the fidelity of transcriptional initiation in vivo. Mol. Cell. Biol. 23, 8323–8333 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Heo, K. et al. FACT-mediated exchange of histone variant H2AX regulated by phosphorylation of H2AX and ADP-ribosylation of Spt16. Mol. Cell 30, 86–97 (2008).

    CAS  PubMed  Google Scholar 

  51. Hondele, M. et al. Structural basis of histone H2A–H2B recognition by the essential chaperone FACT. Nature 499, 111–114 (2013).

    CAS  PubMed  Google Scholar 

  52. Kemble, D. J., McCullough, L. L., Whitby, F. G., Formosa, T. & Hill, C. P. FACT disrupts nucleosome structure by binding H2A–H2B with conserved peptide motifs. Mol. Cell 60, 294–306 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Yang, J. et al. The histone chaperone FACT contributes to DNA replication-coupled nucleosome assembly. Cell Rep. 14, 1128–1141 (2016).

    CAS  PubMed  Google Scholar 

  54. Ramachandran, S. & Henikoff, S. Replicating nucleosomes. Sci. Adv. 1, e1500587 (2015).

    PubMed  PubMed Central  Google Scholar 

  55. Shibahara, K. & Stillman, B. Replication-dependent marking of DNA by PCNA facilitates CAF-1-coupled inheritance of chromatin. Cell 96, 575–585 (1999).

    CAS  PubMed  Google Scholar 

  56. Natsume, R. et al. Structure and function of the histone chaperone CIA/ASF1 complexed with histones H3 and H4. Nature 446, 338–341 (2007).

    CAS  PubMed  Google Scholar 

  57. Winkler, D. D., Zhou, H., Dar, M. A., Zhang, Z. & Luger, K. Yeast CAF-1 assembles histone (H3–H4)2 tetramers prior to DNA deposition. Nucleic Acids Res. 40, 10139–10149 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Xu, M. et al. Partitioning of histone H3–H4 tetramers during DNA replication-dependent chromatin assembly. Science 328, 94–98 (2010).

    CAS  PubMed  Google Scholar 

  59. Foltman, M. et al. Eukaryotic replisome components cooperate to process histones during chromosome replication. Cell Rep. 3, 892–904 (2013).

    CAS  PubMed  Google Scholar 

  60. Richet, N. et al. Structural insight into how the human helicase subunit MCM2 may act as a histone chaperone together with ASF1 at the replication fork. Nucleic Acids Res. 43, 1905–1917 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Huang, H. et al. A unique binding mode enables MCM2 to chaperone histones H3–H4 at replication forks. Nat. Struct. Mol. Biol. 22, 618–626 (2015). The MCM2 subunit of the replicative helicase co-chaperones with ASF1 H3–H4 dimers regardless of variant composition.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Houlard, M. et al. CAF-1 is essential for heterochromatin organization in pluripotent embryonic cells. PLoS Genet. 2, e181 (2006).

    PubMed  PubMed Central  Google Scholar 

  63. Kaya, H. et al. FASCIATA genes for chromatin assembly factor-1 in Arabidopsis maintain the cellular organization of apical meristems. Cell 104, 131–142 (2001).

    CAS  PubMed  Google Scholar 

  64. Duc, C. et al. The histone chaperone complex HIR maintains nucleosome occupancy and counterbalances impaired histone deposition in CAF-1 complex mutants. Plant J. 81, 707–722 (2015).

    CAS  PubMed  Google Scholar 

  65. Alabert, C. et al. Two distinct modes for propagation of histone PTMs across the cell cycle. Genes Dev. 29, 585–590 (2015). Most histone modifications are restored rapidly after replication, but H2A.Z levels are only slowly restored over the course of multiple cell generations.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Xu, M., Wang, W., Chen, S. & Zhu, B. A model for mitotic inheritance of histone lysine methylation. EMBO Rep. 13, 60–67 (2012).

    CAS  Google Scholar 

  67. Jeronimo, C., Watanabe, S., Kaplan, C. D., Peterson, C. L. & Robert, F. The histone chaperones FACT and Spt6 restrict H2A.Z from intragenic locations. Mol. Cell 58, 1113–1123 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Tran, V., Lim, C., Xie, J. & Chen, X. Asymmetric division of Drosophila male germline stem cell shows asymmetric histone distribution. Science 338, 679–682 (2012). Asymmetric division of germline stem cells in D. melanogaster testes results in newly deposited H3.1, but not H3.3, segregating to the progenitor cell with retention of old H3.1 in the self-renewing stem cell.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Xie, J. et al. Histone H3 threonine phosphorylation regulates asymmetric histone inheritance in the Drosophila male germline. Cell 163, 920–933 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Studitsky, V. M., Clark, D. J. & Felsenfeld, G. A histone octamer can step around a transcribing polymerase without leaving the template. Cell 76, 371–382 (1994).

    CAS  PubMed  Google Scholar 

  71. Kornberg, R. D. & Lorch, Y. Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 98, 285–294 (1999).

    CAS  PubMed  Google Scholar 

  72. Bernstein, B. E., Liu, C. L., Humphrey, E. L., Perlstein, E. O. & Schreiber, S. L. Global nucleosome occupancy in yeast. Genome Biol. 5, R62 (2004).

    PubMed  PubMed Central  Google Scholar 

  73. Lee, C. K., Shibata, Y., Rao, B., Strahl, B. D. & Lieb, J. D. Evidence for nucleosome depletion at active regulatory regions genome-wide. Nat. Genet. 36, 900–905 (2004).

    CAS  PubMed  Google Scholar 

  74. Dion, M. F. et al. Dynamics of replication-independent histone turnover in budding yeast. Science 315, 1405–1408 (2007).

    CAS  PubMed  Google Scholar 

  75. Jamai, A., Imoberdorf, R. M. & Strubin, M. Continuous histone H2B and transcription-dependent histone H3 exchange in yeast cells outside of replication. Mol. Cell 25, 345–355 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Raisner, R. M. et al. Histone variant H2A.Z marks the 5′ ends of both active and inactive genes in euchromatin. Cell 123, 233–248 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Rhee, H. S. & Pugh, B. F. Genome-wide structure and organization of eukaryotic pre-initiation complexes. Nature 483, 295–301 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Mizuguchi, G. et al. ATP-driven exchange of histone H2AZ variant catalyzed by SWR1 chromatin remodeling complex. Science 303, 343–348 (2004).

    CAS  PubMed  Google Scholar 

  80. 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 

  81. Papamichos-Chronakis, M., Watanabe, S., Rando, O. J. & Peterson, C. L. Global regulation of H2A.Z localization by the INO80 chromatin-remodeling enzyme is essential for genome integrity. Cell 144, 200–213 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Guillemette, B. et al. Variant histone H2A.Z is globally localized to the promoters of inactive yeast genes and regulates nucleosome positioning. PLoS Biol. 3, e384 (2005).

    PubMed  PubMed Central  Google Scholar 

  83. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Zanton, S. J. & Pugh, B. F. Full and partial genome-wide assembly and disassembly of the yeast transcription machinery in response to heat shock. Genes Dev. 20, 2250–2265 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Tramantano, M. et al. Constitutive turnover of histone H2A.Z at yeast promoters requires the preinitiation complex. eLife 5, e14243 (2016). Components of the transcription pre-initiation complex cause H2A.Z turnover in budding yeast.

    PubMed  PubMed Central  Google Scholar 

  86. Meneghini, M. D., Wu, M. & Madhani, H. D. Conserved histone variant H2A.Z protects euchromatin from the ectopic spread of silent heterochromatin. Cell 112, 725–736 (2003).

    CAS  PubMed  Google Scholar 

  87. Ramachandran, S., Zentner, G. E. & Henikoff, S. Asymmetric nucleosomes flank promoters in the budding yeast genome. Genome Res. 25, 381–390 (2015). Half-unwrapping of RSC-bound nucleosomes flanking promoters in vivo indicates that RSC partially unwraps a nucleosome before performing ATP-dependent DNA translocation.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Lorch, Y., Maier-Davis, B. & Kornberg, R. D. Mechanism of chromatin remodeling. Proc. Natl Acad. Sci. USA 107, 3458–3462 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Adkins, M. W. & Tyler, J. K. Transcriptional activators are dispensable for transcription in the absence of Spt6-mediated chromatin reassembly of promoter regions. Mol. Cell 21, 405–416 (2006).

    CAS  PubMed  Google Scholar 

  90. Jamai, A., Puglisi, A. & Strubin, M. Histone chaperone Spt16 promotes redeposition of the original H3–H4 histones evicted by elongating RNA polymerase. Mol. Cell 35, 377–383 (2009).

    CAS  PubMed  Google Scholar 

  91. Kato, H. et al. Spt6 prevents transcription-coupled loss of posttranslationally modified histone H3. Sci. Rep. 3, 2186 (2013).

    PubMed  PubMed Central  Google Scholar 

  92. Kaplan, C. D., Morris, J. R., Wu, C. & Winston, F. Spt5 and Spt6 are associated with active transcription and have characteristics of general elongation factors in D. melanogaster. Genes Dev. 14, 2623–2634 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Hartzog, G. A., Wada, T., Handa, H. & Winston, F. Evidence that Spt4, Spt5, and Spt6 control transcription elongation by RNA polymerase II in Saccharomyces cerevisiae. Genes Dev. 12, 357–369 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Svensson, J. P. et al. A nucleosome turnover map reveals that the stability of histone H4 Lys20 methylation depends on histone recycling in transcribed chromatin. Genome Res. 25, 872–883 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Deal, R. B., Henikoff, J. G. & Henikoff, S. Genome-wide kinetics of nucleosome turnover determined by metabolic labeling of histones. Science 328, 1161–1164 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Mito, Y., Henikoff, J. G. & Henikoff, S. Genome-scale profiling of histone H3.3 replacement patterns. Nat. Genet. 37, 1090–1097 (2005).

    CAS  PubMed  Google Scholar 

  99. Mito, Y., Henikoff, J. G. & Henikoff, S. Histone replacement marks the boundaries of cis-regulatory domains. Science 315, 1408–1411 (2007).

    CAS  PubMed  Google Scholar 

  100. Wirbelauer, C., Bell, O. & Schubeler, D. Variant histone H3.3 is deposited at sites of nucleosomal displacement throughout transcribed genes while active histone modifications show a promoter-proximal bias. Genes Dev. 19, 1761–1766 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Nakayama, T., Nishioka, K., Dong, Y. X., Shimojima, T. & Hirose, S. Drosophila GAGA factor directs histone H3.3 replacement that prevents the heterochromatin spreading. Genes Dev. 21, 552–561 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Chow, C. M. et al. Variant histone H3.3 marks promoters of transcriptionally active genes during mammalian cell division. EMBO Rep. 6, 354–360 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Jin, C. & Felsenfeld, G. Distribution of histone H3.3 in hematopoietic cell lineages. Proc. Natl Acad. Sci. USA 103, 574–579 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Kraushaar, D. C. et al. Genome-wide incorporation dynamics reveal distinct categories of turnover for the histone variant H3.3. Genome Biol. 14, R121 (2013).

    PubMed  PubMed Central  Google Scholar 

  106. Deaton, A. M. et al. Enhancer regions show high histone H3.3 turnover that changes during differentiation. eLife 5, e15316 (2016). Active enhancers are characterized by high turnover of H3.3 during differentiation.

    PubMed  PubMed Central  Google Scholar 

  107. 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 

  108. Huang, C. et al. H3.3–H4 tetramer splitting events feature cell-type specific enhancers. PLoS Genet. 9, e1003558 (2013). Although H3.1-containing nucleosomes are reassembled with an intact four-helix bundle behind the replication fork, H3.3 nucleosomes at enhancers tend to split.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 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 

  110. 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 

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

    CAS  PubMed  Google Scholar 

  112. Nishibuchi, I. et al. Reorganization of damaged chromatin by the exchange of histone variant H2A.Z-2. Int. J. Radiat. Oncol. Biol. Phys. 89, 736–744 (2014).

    CAS  PubMed  Google Scholar 

  113. 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 

  114. Horikoshi, N. et al. Structural polymorphism in the L1 loop regions of human H2A.Z.1 and H2A.Z.2. Acta Crystallogr. D Biol. Crystallogr. 69, 2431–2439 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Horikoshi, N., Arimura, Y., Taguchi, H. & Kurumizaka, H. Crystal structures of heterotypic nucleosomes containing histones H2A.Z and H2A. Open Biol. 6, 160127 (2016).

    PubMed  PubMed Central  Google Scholar 

  116. Kubik, S. et al. Nucleosome stability distinguishes two different promoter types at all protein-coding genes in yeast. Mol. Cell 60, 422–434 (2015). In budding yeast, fragile nucleosomes form in nucleosome-depleted regions that are widened by the binding of general regulatory factors.

    CAS  PubMed  Google Scholar 

  117. Pradhan, S. K. et al. EP400 deposits H3.3 into promoters and enhancers during gene activation. Mol. Cell 61, 27–38 (2016).

    CAS  PubMed  Google Scholar 

  118. Weber, C. M., Henikoff, J. G. & Henikoff, S. H2A.Z nucleosomes enriched over active genes are homotypic. Nat. Struct. Mol. Biol. 17, 1500–1507 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Weber, C. M., Ramachandran, S. & Henikoff, S. Nucleosomes are context-specific, H2A.Z-modulated barriers to RNA polymerase. Mol. Cell 53, 819–830 (2014). Nucleosome barriers to Pol II are lowered by H2A.Z in vivo.

    CAS  PubMed  Google Scholar 

  120. Nekrasov, M. et al. Histone H2A.Z inheritance during the cell cycle and its impact on promoter organization and dynamics. Nat. Struct. Mol. Biol. 19, 1076–1083 (2012).

    CAS  PubMed  Google Scholar 

  121. 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 

  122. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Stroud, H. et al. Genome-wide analysis of histone H3.1 and H3.3 variants in Arabidopsis thaliana. Proc. Natl Acad. Sci. USA 109, 5370–5375 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Wollmann, H. et al. Dynamic deposition of histone variant H3.3 accompanies developmental remodeling of the Arabidopsis transcriptome. PLoS Genet. 8, e1002658 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Coleman-Derr, D. & Zilberman, D. Deposition of histone variant H2A.Z within gene bodies regulates responsive genes. PLoS Genet. 8, e1002988 (2012). H2A.Z in plants acts as a general sensor of environmental conditions.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Bewick, A. J. et al. On the origin and evolutionary consequences of gene body DNA methylation. Proc. Natl Acad. Sci. USA 113, 9111–9116 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Kumar, S. V. & Wigge, P. A. H2A.Z-containing nucleosomes mediate the thermosensory response in Arabidopsis. Cell 140, 136–147 (2010).

    CAS  PubMed  Google Scholar 

  128. Coleman-Derr, D. & Zilberman, D. DNA methylation, H2A.Z, and the regulation of constitutive expression. Cold Spring Harb. Symp. Quant. Biol. 77, 147–154 (2012).

    CAS  PubMed  Google Scholar 

  129. Voon, H. P. et al. ATRX plays a key role in maintaining silencing at interstitial heterochromatic loci and imprinted genes. Cell Rep. 11, 405–418 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Elsasser, S. J., Noh, K. M., Diaz, N., Allis, C. D. & Banaszynski, L. A. Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells. Nature 522, 240–244 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. He, Q. et al. The Daxx/Atrx complex protects tandem repetitive elements during DNA hypomethylation by promoting H3K9 trimethylation. Cell Stem Cell 17, 273–286 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Sadic, D. et al. Atrx promotes heterochromatin formation at retrotransposons. EMBO Rep. 16, 836–850 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Valle-Garcia, D. et al. ATRX binds to atypical chromatin domains at the 3′ exons of zinc finger genes to preserve H3K9me3 enrichment. Epigenetics 11, 398–414 (2016).

    PubMed  PubMed Central  Google Scholar 

  134. Dhayalan, A. et al. The ATRX-ADD domain binds to H3 tail peptides and reads the combined methylation state of K4 and K9. Hum. Mol. Genet. 20, 2195–2203 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Eustermann, S. et al. Combinatorial readout of histone H3 modifications specifies localization of ATRX to heterochromatin. Nat. Struct. Mol. Biol. 18, 777–782 (2011).

    CAS  PubMed  Google Scholar 

  136. McDowell, T. L. et al. Localization of a putative transcriptional regulator (ATRX) at pericentromeric heterochromatin and the short arms of acrocentric chromosomes. Proc. Natl Acad. Sci. USA 96, 13983–13988 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Nan, X. et al. Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation. Proc. Natl Acad. Sci. USA 104, 2709–2714 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Law, M. J. et al. ATR-X syndrome protein targets tandem repeats and influences allele-specific expression in a size-dependent manner. Cell 143, 367–378 (2010).

    CAS  PubMed  Google Scholar 

  139. Udugama, M. et al. Histone variant H3.3 provides the heterochromatic H3 lysine 9 tri-methylation mark at telomeres. Nucleic Acids Res. 43, 10227–10237 (2015). H3.3 deposited by ATRX at mammalian telomeres is the preferred substrate for H3K9 trimethylation and heterochromatin formation.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Basavapathruni, A. et al. Characterization of the enzymatic activity of SETDB1 and its 1:1 complex with ATF7IP. Biochemistry 55, 1645–1651 (2016).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Lavigne, M. D. et al. Composite macroH2A/NRF-1 nucleosomes suppress noise and generate robustness in gene expression. Cell Rep. 11, 1090–1101 (2015).

    CAS  PubMed  Google Scholar 

  143. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 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 

  145. Rangasamy, D., Greaves, I. & Tremethick, D. J. RNA interference demonstrates a novel role for H2A.Z in chromosome segregation. Nat. Struct. Mol. Biol. 11, 650–655 (2004).

    CAS  PubMed  Google Scholar 

  146. 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 

  147. Boyarchuk, E., Filipescu, D., Vassias, I., Cantaloube, S. & Almouzni, G. The histone variant composition of centromeres is controlled by the pericentric heterochromatin state during the cell cycle. J. Cell Sci. 127, 3347–3359 (2014).

    CAS  PubMed  Google Scholar 

  148. 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).

    CAS  PubMed  Google Scholar 

  149. Yuan, W. et al. Dense chromatin activates Polycomb repressive complex 2 to regulate H3 lysine 27 methylation. Science 337, 971–975 (2012).

    CAS  PubMed  Google Scholar 

  150. Yi, J., Stypula-Cyrus, Y., Blaha, C. S., Roy, H. K. & Backman, V. Fractal characterization of chromatin decompaction in live cells. Biophys. J. 109, 2218–2226 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Hsieh, F. K. et al. Histone chaperone FACT action during transcription through chromatin by RNA polymerase II. Proc. Natl Acad. Sci. USA 110, 7654–7659 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Xin, H. et al. yFACT induces global accessibility of nucleosomal DNA without H2A–H2B displacement. Mol. Cell 35, 365–376 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Obri, A. et al. ANP32E is a histone chaperone that removes H2A.Z from chromatin. Nature 505, 648–653 (2014).

    CAS  PubMed  Google Scholar 

  154. Hong, J. et al. The catalytic subunit of the SWR1 remodeler is a histone chaperone for the H2A.Z–H2B dimer. Mol. Cell 53, 498–505 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Brunelle, M. et al. The histone variant H2A.Z is an important regulator of enhancer activity. Nucleic Acids Res. 43, 9742–9756 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Dalvai, M., Fleury, L., Bellucci, L., Kocanova, S. & Bystricky, K. TIP48/reptin and H2A.Z requirement for initiating chromatin remodeling in estrogen-activated transcription. PLoS Genet. 9, e1003387 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Chuang, L. S. et al. Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. Science 277, 1996–2000 (1997).

    CAS  PubMed  Google Scholar 

  158. Sarraf, S. A. & Stancheva, I. Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly. Mol. Cell 15, 595–605 (2004).

    CAS  PubMed  Google Scholar 

  159. Loyola, A. et al. The HP1α-CAF1-SetDB1-containing complex provides H3K9me1 for Suv39-mediated K9me3 in pericentric heterochromatin. EMBO Rep. 10, 769–775 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Souza, P. P. et al. The histone methyltransferase SUV420H2 and heterochromatin proteins HP1 interact but show different dynamic behaviours. BMC Cell Biol. 10, 41 (2009).

    PubMed  PubMed Central  Google Scholar 

  161. Krouwels, I. M. et al. A glue for heterochromatin maintenance: stable SUV39H1 binding to heterochromatin is reinforced by the SET domain. J. Cell Biol. 170, 537–549 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Fischer, A., Hofmann, I., Naumann, K. & Reuter, G. Heterochromatin proteins and the control of heterochromatic gene silencing in Arabidopsis. J. Plant Physiol. 163, 358–368 (2006).

    CAS  PubMed  Google Scholar 

  163. Raynaud, C. et al. Two cell-cycle regulated SET-domain proteins interact with proliferating cell nuclear antigen (PCNA) in Arabidopsis. Plant J. 47, 395–407 (2006).

    CAS  PubMed  Google Scholar 

  164. Jacob, Y. et al. Selective methylation of histone H3 variant H3.1 regulates heterochromatin replication. Science 343, 1249–1253 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank K. Ahmad, S. Ramachandran, S. Kasinathan and anonymous reviewers for their helpful comments on the manuscript.

Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, 98109–1024, Washington, USA

    Paul B. Talbert & Steven Henikoff

Authors
  1. Paul B. Talbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steven Henikoff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Paul B. Talbert or Steven Henikoff.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

Major Histone dimers and chaperones (PDF 79 kb)

Supplementary information S2 (box)

Major chaperones in the cytosol (PDF 119 kb)

PowerPoint slides

Glossary

DNA translocase

A conserved domain of chromatin remodellers that uses ATP to move nucleosomes along DNA.

General regulatory factors

Abundant transcription factors that are found at many promoters and augment the activity of adjacent transcription factors.

Highly positioned nucleosomes

Nucleosomes that occupy the same position on the DNA in a large majority of cells in a population.

Bivalent promoters

Transcription start sites flanked by nucleosomes that are enriched for trimethylation of both the Lys 4 and Lys 27 residues of histone H3, thereby comprising a mark of 'poised' activation.

Docking domain

The carboxy-terminal region of H2A variants, which interacts with H3 and H4.

CTCF

A protein that binds the motif CCCTC and regulates the formation of long-range chromatin interactions and of topologically associated domains.

Fragile nucleosomes

A nucleosome with increased sensitivity to micrococcal nuclease, which forms at yeast promoters that have a nucleosome-depleted region >150 bp.

G-quadruplexes

A four-stranded helical structure formed in DNA and RNA that is composed of four runs of three or more guanines, separated by up to seven other nucleotides.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Talbert, P., Henikoff, S. Histone variants on the move: substrates for chromatin dynamics. Nat Rev Mol Cell Biol 18, 115–126 (2017). https://doi.org/10.1038/nrm.2016.148

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm.2016.148

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