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Emerging roles of linker histones in regulating chromatin structure and function

Nature Reviews Molecular Cell Biology volume 19, pages 192–206 (2018)Cite this article

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Key Points

  • Studies using X-ray crystallography, NMR and cryo-electron microscopy (cryo-EM) reveal that linker histones (H1) bind to nucleosomes via electrostatic interactions and that this binding can occur in either on-dyad or off-dyad mode. These different binding modes can lead to differential folding of nucleosome arrays, with different levels of compaction.

  • Cryo-EM studies reveal that 30 nm nucleosome arrays form a twisted double helix with the tetra-nucleosome as the structural unit, in which human linker histone variant H1.4 binds off the nucleosome dyad. Folding of the nucleosome array may potentially affect the binding mode of the linker histone. There is evidence that in vivo chromatin fibres in the presence of linker histones are formed by heterogeneous groups of nucleosomes with different sizes, termed 'nucleosome clutches'.

  • In addition to the regulation of chromatin structure, H1 is intimately involved in the control of multiple chromatin metabolism processes, such as DNA replication and repair, as well as modulation of the epigenetic landscape of the genome.

  • The occupancy of H1 in chromosomes is not uniform. The dynamic, locus-specific, activity- and cell cycle-dependent distribution of H1 has essential implications for its biological activities.

  • At the molecular level, H1 acts in a variety of distinct, biochemically separable mechanisms, including chromatin fibre compaction and limiting DNA accessibility to DNA-binding proteins, as well as tethering or specific inhibition of nuclear enzymes.

Abstract

Together with core histones, which make up the nucleosome, the linker histone (H1) is one of the five main histone protein families present in chromatin in eukaryotic cells. H1 binds to the nucleosome to form the next structural unit of metazoan chromatin, the chromatosome, which may help chromatin to fold into higher-order structures. Despite their important roles in regulating the structure and function of chromatin, linker histones have not been studied as extensively as core histones. Nevertheless, substantial progress has been made recently. The first near-atomic resolution crystal structure of a chromatosome core particle and an 11 Å resolution cryo-electron microscopy-derived structure of the 30 nm nucleosome array have been determined, revealing unprecedented details about how linker histones interact with the nucleosome and organize higher-order chromatin structures. Moreover, several new functions of linker histones have been discovered, including their roles in epigenetic regulation and the regulation of DNA replication, DNA repair and genome stability. Studies of the molecular mechanisms of H1 action in these processes suggest a new paradigm for linker histone function beyond its architectural roles in chromatin.

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Figure 1: Multiple levels of chromatin folding.
Figure 2: Structural illustration of the folded core regions of a chromatosome and representative interactions between histones and DNA.
Figure 3: Roles of linker histones in chromatin folding.
Figure 4: Biological functions of linker histones.
Figure 5: Biochemical activities of linker histones.

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References

  1. Olins, A. L. & Olins, D. E. Spheroid chromatin units (v bodies). Science 183, 330–332 (1974).

    Article  CAS  PubMed  Google Scholar 

  2. Kornberg, R. D. Chromatin structure: a repeating unit of histones and DNA. Science 184, 868–871 (1974).

    Article  CAS  PubMed  Google Scholar 

  3. Kornberg, R. D. & Thomas, J. O. Chromatin structure; oligomers of the histones. Science 184, 865–868 (1974).

    Article  CAS  PubMed  Google Scholar 

  4. Arents, G. & Moudrianakis, E. N. Topography of the histone octamer surface: repeating structural motifs utilized in the docking of nucleosomal DNA. Proc. Natl Acad. Sci. USA 90, 10489–10493 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. 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).

    Article  CAS  PubMed  Google Scholar 

  6. Noll, M. & Kornberg, R. D. Action of micrococcal nuclease on chromatin and the location of histone H1. J. Mol. Biol. 109, 393–404 (1977).

    Article  CAS  PubMed  Google Scholar 

  7. Simpson, R. T. Structure of the chromatosome, a chromatin particle containing 160 base pairs of DNA and all the histones. Biochemistry 17, 5524–5531 (1978). This study defines the chromatosome core particle for the first time.

    Article  CAS  PubMed  Google Scholar 

  8. Thoma, F., Koller, T. & Klug, A. Involvement of histone H1 in the organization of the nucleosome and of the salt-dependent superstructures of chromatin. J. Cell Biol. 83, 403–427 (1979).

    Article  CAS  PubMed  Google Scholar 

  9. Allan, J., Hartman, P. G., Crane-Robinson, C. & Aviles, F. X. The structure of histone H1 and its location in chromatin. Nature 288, 675–679 (1980).

    Article  CAS  PubMed  Google Scholar 

  10. Allan, J., Mitchell, T., Harborne, N., Bohm, L. & Crane-Robinson, C. Roles of H1 domains in determining higher order chromatin structure and H1 location. J. Mol. Biol. 187, 591–601 (1986).

    Article  CAS  PubMed  Google Scholar 

  11. Ramakrishnan, V., Finch, J. T., Graziano, V., Lee, P. L. & Sweet, R. M. Crystal structure of globular domain of histone H5 and its implications for nucleosome binding. Nature 362, 219–223 (1993).

    Article  CAS  PubMed  Google Scholar 

  12. Singer, D. S. & Singer, M. F. Studies on the interaction of H1 histone with superhelical DNA: characterization of the recognition and binding regions of H1 histones. Nucleic Acids Res. 3, 2531–2547 (1976).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lorch, Y., LaPointe, J. W. & Kornberg, R. D. Nucleosomes inhibit the initiation of transcription but allow chain elongation with the displacement of histones. Cell 49, 203–210 (1987).

    Article  CAS  PubMed  Google Scholar 

  14. Nagai, S., Davis, R. E., Mattei, P. J., Eagen, K. P. & Kornberg, R. D. Chromatin potentiates transcription. Proc. Natl Acad. Sci. USA 114, 1536–1541 (2017).

    Article  CAS  PubMed  Google Scholar 

  15. Izzo, A. & Schneider, R. The role of linker histone H1 modifications in the regulation of gene expression and chromatin dynamics. Biochim. Biophys. Acta 1859, 486–495 (2016).

    Article  CAS  PubMed  Google Scholar 

  16. Allis, C. D. & Jenuwein, T. The molecular hallmarks of epigenetic control. Nat. Rev. Genet. 17, 487–500 (2016).

    Article  CAS  PubMed  Google Scholar 

  17. Eberharter, A. & Becker, P. B. Histone acetylation: a switch between repressive and permissive chromatin. Second in review series on chromatin dynamics. EMBO Rep. 3, 224–229 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Torres, I. O. & Fujimori, D. G. Functional coupling between writers, erasers and readers of histone and DNA methylation. Curr. Opin. Struct. Biol. 35, 68–75 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hammond, C. M., Stromme, C. B., Huang, H., Patel, D. J. & Groth, A. Histone chaperone networks shaping chromatin function. Nat. Rev. Mol. Cell Biol. 18, 141–158 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shintomi, K. et al. Nucleosome assembly protein-1 is a linker histone chaperone in Xenopus eggs. Proc. Natl Acad. Sci. USA 102, 8210–8215 (2005).

    Article  CAS  PubMed  Google Scholar 

  21. Richardson, R. T. et al. Nuclear autoantigenic sperm protein (NASP), a linker histone chaperone that is required for cell proliferation. J. Biol. Chem. 281, 21526–21534 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Fan, Y. et al. Histone H1 depletion in mammals alters global chromatin structure but causes specific changes in gene regulation. Cell 123, 1199–1212 (2005). This study shows for the first time that H1 participates in epigenetic regulation in vivo by affecting DNA methylation at specific loci.

    Article  CAS  PubMed  Google Scholar 

  23. Hergeth, S. P. & Schneider, R. The H1 linker histones: multifunctional proteins beyond the nucleosomal core particle. EMBO Rep. 16, 1439–1453 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bates, D. L. & Thomas, J. O. Histones H1 and H5: one or two molecules per nucleosome? Nucleic Acids Res. 9, 5883–5894 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. Kowalski, A. & Palyga, J. Modulation of chromatin function through linker histone H1 variants. Biol. Cell 108, 339–356 (2016).

    Article  CAS  PubMed  Google Scholar 

  27. Christophorou, M. A. et al. Citrullination regulates pluripotency and histone H1 binding to chromatin. Nature 507, 104–108 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Torres, C. M. et al. The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity. Science 353, aaf1644 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Richmond, T. J. & Davey, C. A. The structure of DNA in the nucleosome core. Nature 423, 145–150 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Geeven, G. et al. Local compartment changes and regulatory landscape alterations in histone H1-depleted cells. Genome Biol. 16, 289 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Thoma, F. & Koller, T. Influence of histone H1 on chromatin structure. Cell 12, 101–107 (1977).

    Article  CAS  PubMed  Google Scholar 

  32. Pruss, D. et al. An asymmetric model for the nucleosome: a binding site for linker histones inside the DNA gyres. Science 274, 614–617 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Zhou, Y. B., Gerchman, S. E., Ramakrishnan, V., Travers, A. & Muyldermans, S. Position and orientation of the globular domain of linker histone H5 on the nucleosome. Nature 395, 402–405 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. An, W., Leuba, S. H., van Holde, K. & Zlatanova, J. Linker histone protects linker DNA on only one side of the core particle and in a sequence-dependent manner. Proc. Natl Acad. Sci. USA 95, 3396–3401 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Fan, L. & Roberts, V. A. Complex of linker histone H5 with the nucleosome and its implications for chromatin packing. Proc. Natl Acad. Sci. USA 103, 8384–8389 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Brown, D. T., Izard, T. & Misteli, T. Mapping the interaction surface of linker histone H1(0) with the nucleosome of native chromatin in vivo. Nat. Struct. Mol. Biol. 13, 250–255 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cui, F. & Zhurkin, V. B. Distinctive sequence patterns in metazoan and yeast nucleosomes: implications for linker histone binding to AT-rich and methylated DNA. Nucleic Acids Res. 37, 2818–2829 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Syed, S. H. et al. Single-base resolution mapping of H1-nucleosome interactions and 3D organization of the nucleosome. Proc. Natl Acad. Sci. USA 107, 9620–9625 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Pachov, G. V., Gabdoulline, R. R. & Wade, R. C. On the structure and dynamics of the complex of the nucleosome and the linker histone. Nucleic Acids Res. 39, 5255–5263 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhou, B. R. et al. Structural mechanisms of nucleosome recognition by linker histones. Mol. Cell 59, 628–638 (2015). This paper presents the first near-atomic resolution crystal structure of the nucleosome bound to the globular domain of chicken H5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Goytisolo, F. A. et al. Identification of two DNA-binding sites on the globular domain of histone H5. EMBO J. 15, 3421–3429 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Duggan, M. M. & Thomas, J. O. Two DNA-binding sites on the globular domain of histone H5 are required for binding to both bulk and 5 S reconstituted nucleosomes. J. Mol. Biol. 304, 21–33 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Zhou, B. R. et al. A small number of residues can determine if linker histones are bound on or off dyad in the chromatosome. J. Mol. Biol. 428, 3948–3959 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bednar, J. et al. Structure and dynamics of a 197 bp nucleosome in complex with linker histone H1. Mol. Cell 66, 384–397.e8 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. White, A. E., Hieb, A. R. & Luger, K. A quantitative investigation of linker histone interactions with nucleosomes and chromatin. Sci. Rep. 6, 19122 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhou, B. R. et al. Structural insights into the histone H1-nucleosome complex. Proc. Natl Acad. Sci. USA 110, 19390–19395 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Song, F. et al. Cryo-EM study of the chromatin fiber reveals a double helix twisted by tetranucleosomal units. Science 344, 376–380 (2014). This paper presents the first cryo-EM structure of the 30 nm nucleosome array containing human linker histone variant H1.4, in which the linker histone is visible and binds off the nucleosome dyad.

    Article  CAS  PubMed  Google Scholar 

  48. Finch, J. T. & Klug, A. Solenoidal model for superstructure in chromatin. Proc. Natl Acad. Sci. USA 73, 1897–1901 (1976).

    Article  CAS  PubMed  Google Scholar 

  49. McGhee, J. D., Nickol, J. M., Felsenfeld, G. & Rau, D. C. Higher order structure of chromatin: orientation of nucleosomes within the 30 nm chromatin solenoid is independent of species and spacer length. Cell 33, 831–841 (1983).

    Article  CAS  PubMed  Google Scholar 

  50. Widom, J. & Klug, A. Structure of the 300Å chromatin filament: x-ray diffraction from oriented samples. Cell 43, 207–213 (1985).

    Article  CAS  PubMed  Google Scholar 

  51. Ghirlando, R. & Felsenfeld, G. Hydrodynamic studies on defined heterochromatin fragments support a 30 nm fiber having six nucleosomes per turn. J. Mol. Biol. 376, 1417–1425 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Worcel, A., Strogatz, S. & Riley, D. Structure of chromatin and the linking number of DNA. Proc. Natl Acad. Sci. USA 78, 1461–1465 (1981).

    Article  CAS  PubMed  Google Scholar 

  53. Williams, S. P. et al. Chromatin fibers are left-handed double helices with diameter and mass per unit length that depend on linker length. Biophys. J. 49, 233–248 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Woodcock, C. L., Frado, L. L. & Rattner, J. B. The higher-order structure of chromatin: evidence for a helical ribbon arrangement. J. Cell Biol. 99, 42–52 (1984).

    Article  CAS  PubMed  Google Scholar 

  55. Dorigo, B. et al. Nucleosome arrays reveal the two-start organization of the chromatin fiber. Science 306, 1571–1573 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Schalch, T., Duda, S., Sargent, D. F. & Richmond, T. J. X-ray structure of a tetranucleosome and its implications for the chromatin fibre. Nature 436, 138–141 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Routh, A., Sandin, S. & Rhodes, D. Nucleosome repeat length and linker histone stoichiometry determine chromatin fiber structure. Proc. Natl Acad. Sci. USA 105, 8872–8877 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Robinson, P. J. & Rhodes, D. Structure of the '30 nm' chromatin fibre: a key role for the linker histone. Curr. Opin. Struct. Biol. 16, 336–343 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Maeshima, K., Imai, R., Tamura, S. & Nozaki, T. Chromatin as dynamic 10-nm fibers. Chromosoma 123, 225–237 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Scheffer, M. P., Eltsov, M. & Frangakis, A. S. Evidence for short-range helical order in the 30-nm chromatin fibers of erythrocyte nuclei. Proc. Natl Acad. Sci. USA 108, 16992–16997 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Robinson, P. J., Fairall, L., Huynh, V. A. & Rhodes, D. EM measurements define the dimensions of the “30-nm” chromatin fiber: evidence for a compact, interdigitated structure. Proc. Natl Acad. Sci. USA 103, 6506–6511 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Bednar, J. et al. Nucleosomes, linker DNA, and linker histone form a unique structural motif that directs the higher-order folding and compaction of chromatin. Proc. Natl Acad. Sci. USA 95, 14173–14178 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Ricci, M. A., Manzo, C., Garcia-Parajo, M. F., Lakadamyali, M. & Cosma, M. P. Chromatin fibers are formed by heterogeneous groups of nucleosomes in vivo. Cell 160, 1145–1158 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Grigoryev, S. A. et al. Hierarchical looping of zigzag nucleosome chains in metaphase chromosomes. Proc. Natl Acad. Sci. USA 113, 1238–1243 (2016).

    Article  CAS  PubMed  Google Scholar 

  65. Li, W. et al. FACT remodels the tetranucleosomal unit of chromatin fibers for gene transcription. Mol. Cell 64, 120–133 (2016).

    Article  CAS  PubMed  Google Scholar 

  66. Nora, E. P. et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485, 381–385 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hou, C., Li, L., Qin, Z. S. & Corces, V. G. Gene density, transcription, and insulators contribute to the partition of the Drosophila genome into physical domains. Mol. Cell 48, 471–484 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sexton, T. et al. Three-dimensional folding and functional organization principles of the Drosophila genome. Cell 148, 458–472 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. Wolffe, A. P. Histone H1. Int. J. Biochem. Cell Biol. 29, 1463–1466 (1997).

    Article  CAS  PubMed  Google Scholar 

  71. Braunschweig, U., Hogan, G. J., Pagie, L. & van Steensel, B. Histone H1 binding is inhibited by histone variant H3.3. EMBO J. 28, 3635–3645 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 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).

    Article  CAS  PubMed  Google Scholar 

  73. Li, J. Y., Patterson, M., Mikkola, H. K., Lowry, W. E. & Kurdistani, S. K. Dynamic distribution of linker histone H1.5 in cellular differentiation. PLoS Genet. 8, e1002879 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Cao, K. et al. High-resolution mapping of h1 linker histone variants in embryonic stem cells. PLoS Genet. 9, e1003417 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Millan-Arino, L. et al. Mapping of six somatic linker histone H1 variants in human breast cancer cells uncovers specific features of H1.2. Nucleic Acids Res. 42, 4474–4493 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Nalabothula, N. et al. The chromatin architectural proteins HMGD1 and H1 bind reciprocally and have opposite effects on chromatin structure and gene regulation. BMC Genomics 15, 92 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Mayor, R. et al. Genome distribution of replication-independent histone H1 variants shows H1.0 associated with nucleolar domains and H1X associated with RNA polymerase II-enriched regions. J. Biol. Chem. 290, 7474–7491 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Reczek, P. R., Weissman, D., Huvos, P. E. & Fasman, G. D. Sodium butyrate induced structural changes in HeLa cell chromatin. Biochemistry 21, 993–1002 (1982).

    Article  CAS  PubMed  Google Scholar 

  79. Schroter, H., Gomez-Lira, M. M., Plank, K. H. & Bode, J. The extent of histone acetylation induced by butyrate and the turnover of acetyl groups depend on the nature of the cell line. Eur. J. Biochem. 120, 21–28 (1981).

    Article  CAS  PubMed  Google Scholar 

  80. Herrera, J. E., West, K. L., Schiltz, R. L., Nakatani, Y. & Bustin, M. Histone H1 is a specific repressor of core histone acetylation in chromatin. Mol. Cell. Biol. 20, 523–529 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Sun, J. et al. Histone H1-mediated epigenetic regulation controls germline stem cell self-renewal by modulating H4K16 acetylation. Nat. Commun. 6, 8856 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Vaquero, A. et al. Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol. Cell 16, 93–105 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Lu, X. et al. Linker histone H1 is essential for Drosophila development, the establishment of pericentric heterochromatin, and a normal polytene chromosome structure. Genes Dev. 23, 452–465 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Iwasaki, Y. W. et al. Piwi modulates chromatin accessibility by regulating multiple factors including histone H1 to repress transposons. Mol. Cell 63, 408–419 (2016). References 84 and 85 elucidate two different mechanisms by which H1 is involved in repression of genetic activity in heterochromatin.

    Article  CAS  PubMed  Google Scholar 

  86. Yang, S. M., Kim, B. J., Norwood Toro, L. & Skoultchi, A. I. H1 linker histone promotes epigenetic silencing by regulating both DNA methylation and histone H3 methylation. Proc. Natl Acad. Sci. USA 110, 1708–1713 (2013).

    Article  CAS  PubMed  Google Scholar 

  87. Stutzer, A. et al. Modulations of DNA contacts by linker histones and post-translational modifications determine the mobility and modifiability of nucleosomal H3 tails. Mol. Cell 61, 247–259 (2016).

    Article  CAS  PubMed  Google Scholar 

  88. Martin, C., Cao, R. & Zhang, Y. Substrate preferences of the EZH2 histone methyltransferase complex. J. Biol. Chem. 281, 8365–8370 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  90. Kim, J. M. et al. Linker histone H1.2 establishes chromatin compaction and gene silencing through recognition of H3K27me3. Scientif. Rep. 5, 16714 (2015).

    Article  CAS  Google Scholar 

  91. Kim, K. et al. Linker histone H1.2 cooperates with Cul4A and PAF1 to drive H4K31 ubiquitylation-mediated transactivation. Cell Rep. 5, 1690–1703 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Du, J., Johnson, L. M., Jacobsen, S. E. & Patel, D. J. DNA methylation pathways and their crosstalk with histone methylation. Nat. Rev. Mol. Cell Biol. 16, 519–532 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wierzbicki, A. T. & Jerzmanowski, A. Suppression of histone H1 genes in Arabidopsis results in heritable developmental defects and stochastic changes in DNA methylation. Genetics 169, 997–1008 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Maclean, J. A. et al. The rhox homeobox gene cluster is imprinted and selectively targeted for regulation by histone H1 and DNA methylation. Mol. Cell. Biol. 31, 1275–1287 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Zhang, Y. et al. Histone H1 depletion impairs embryonic stem cell differentiation. PLoS Genet. 8, e1002691 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Li, H. et al. Mutations in linker histone genes HIST1H1 B, C, D, and E; OCT2 (POU2F2); IRF8; and ARID1A underlying the pathogenesis of follicular lymphoma. Blood 123, 1487–1498 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Flickinger, R. A. Possible role of H1 histone in replication timing. Dev. Growth Differ. 57, 1–9 (2015).

    Article  CAS  PubMed  Google Scholar 

  98. Halmer, L. & Gruss, C. Influence of histone H1 on the in vitro replication of DNA and chromatin. Nucleic Acids Res. 23, 773–778 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Halmer, L. & Gruss, C. Effects of cell cycle dependent histone H1 phosphorylation on chromatin structure and chromatin replication. Nucleic Acids Res. 24, 1420–1427 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lu, Z. H., Sittman, D. B., Brown, D. T., Munshi, R. & Leno, G. H. Histone H1 modulates DNA replication through multiple pathways in Xenopus egg extract. J. Cell Sci. 110, 2745–2758 (1997).

    CAS  PubMed  Google Scholar 

  101. Lu, Z. H., Sittman, D. B., Romanowski, P. & Leno, G. H. Histone H1 reduces the frequency of initiation in Xenopus egg extract by limiting the assembly of prereplication complexes on sperm chromatin. Mol. Biol. Cell 9, 1163–1176 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. De, S. et al. Histone H1 variants differentially inhibit DNA replication through an affinity for chromatin mediated by their carboxyl-terminal domains. Gene 292, 173–181 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Andreyeva, E. N. et al. Regulatory functions and chromatin loading dynamics of linker histone H1 during endoreplication in Drosophila. Genes Dev. 31, 603–616 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Nordman, J. T. et al. DNA copy-number control through inhibition of replication fork progression. Cell Rep. 9, 841–849 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Sher, N. et al. Developmental control of gene copy number by repression of replication initiation and fork progression. Genome Res. 22, 64–75 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Dimitrova, D. S. & Gilbert, D. M. The spatial position and replication timing of chromosomal domains are both established in early G1 phase. Mol. Cell 4, 983–993 (1999).

    Article  CAS  PubMed  Google Scholar 

  107. Thiriet, C. & Hayes, J. J. Linker histone phosphorylation regulates global timing of replication origin firing. J. Biol. Chem. 284, 2823–2829 (2009). References 103 and 107 implicate H1 in the regulation of replication timing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Dou, Y., Mizzen, C. A., Abrams, M., Allis, C. D. & Gorovsky, M. A. Phosphorylation of linker histone H1 regulates gene expression in vivo by mimicking H1 removal. Mol. Cell 4, 641–647 (1999).

    Article  CAS  PubMed  Google Scholar 

  109. Alexandrow, M. G. & Hamlin, J. L. Chromatin decondensation in S-phase involves recruitment of Cdk2 by Cdc45 and histone H1 phosphorylation. J. Cell Biol. 168, 875–886 (2005). References 107, 108 and 109 show the importance of phosphorylation of H1 for its association with chromatin and its effects on gene expression and DNA replication.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Lever, M. A., Th'ng, J. P., Sun, X. & Hendzel, M. J. Rapid exchange of histone H1.1 on chromatin in living human cells. Nature 408, 873–876 (2000).

    Article  CAS  PubMed  Google Scholar 

  111. Downs, J. A., Kosmidou, E., Morgan, A. & Jackson, S. P. Suppression of homologous recombination by the Saccharomyces cerevisiae linker histone. Mol. Cell 11, 1685–1692 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Li, C., Mueller, J. E., Elfline, M. & Bryk, M. Linker histone H1 represses recombination at the ribosomal DNA locus in the budding yeast Saccharomyces cerevisiae. Mol. Microbiol. 67, 906–919 (2008).

    Article  CAS  PubMed  Google Scholar 

  113. Vujatovic, O. et al. Drosophila melanogaster linker histone dH1 is required for transposon silencing and to preserve genome integrity. Nucleic Acids Res. 40, 5402–5414 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hashimoto, H. et al. Histone H1 variant, H1R is involved in DNA damage response. DNA Repair (Amst.) 6, 1584–1595 (2007).

    Article  CAS  Google Scholar 

  115. Murga, M. et al. Global chromatin compaction limits the strength of the DNA damage response. J. Cell Biol. 178, 1101–1108 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Thorslund, T. et al. Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage. Nature 527, 389–393 (2015).

    Article  CAS  PubMed  Google Scholar 

  117. Kalashnikova, A. A. et al. Linker histone H1.0 interacts with an extensive network of proteins found in the nucleolus. Nucleic Acids Res. 41, 4026–4035 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Hamilton, C., Hayward, R. L. & Gilbert, N. Global chromatin fibre compaction in response to DNA damage. Biochem. Biophys. Res. Commun. 414, 820–825 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Sera, T. & Wolffe, A. P. Role of histone H1 as an architectural determinant of chromatin structure and as a specific repressor of transcription on Xenopus oocyte 5S rRNA genes. Mol. Cell. Biol. 18, 3668–3680 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Laybourn, P. J. & Kadonaga, J. T. Role of nucleosomal cores and histone H1 in regulation of transcription by RNA polymerase II. Science 254, 238–245 (1991).

    Article  CAS  PubMed  Google Scholar 

  121. Maier, V. K., Chioda, M., Rhodes, D. & Becker, P. B. ACF catalyses chromatosome movements in chromatin fibres. EMBO J. 27, 817–826 (2008).

    Article  CAS  PubMed  Google Scholar 

  122. Kavi, H. et al. A genetic screen and transcript profiling reveal a shared regulatory program for Drosophila linker histone H1 and chromatin remodeler CHD1. G3 (Bethesda) 5, 677–687 (2015).

    Article  Google Scholar 

  123. Leuba, S. H., Zlatanova, J. & van Holde, K. On the location of linker DNA in the chromatin fiber. Studies with immobilized and soluble micrococcal nuclease. J. Mol. Biol. 235, 871–880 (1994).

    Article  CAS  PubMed  Google Scholar 

  124. Tremethick, D. J. Higher-order structures of chromatin: the elusive 30 nm fiber. Cell 128, 651–654 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Postnikov, Y. V. & Bustin, M. Functional interplay between histone H1 and HMG proteins in chromatin. Biochim. Biophys. Acta 1859, 462–467 (2016).

    Article  CAS  PubMed  Google Scholar 

  126. Krishnakumar, R. et al. Reciprocal binding of PARP-1 and histone H1 at promoters specifies transcriptional outcomes. Science 319, 819–821 (2008). Reference 126 demonstrates a genome-wide, reciprocal binding pattern of H1 and PARP1 and their opposite effects on gene activity, and reference 125 reviews similar competition between H1 and HMG proteins.

    Article  CAS  PubMed  Google Scholar 

  127. Magnani, L., Eeckhoute, J. & Lupien, M. Pioneer factors: directing transcriptional regulators within the chromatin environment. Trends Genet. 27, 465–474 (2011).

    Article  CAS  PubMed  Google Scholar 

  128. Cirillo, L. A. et al. Binding of the winged-helix transcription factor HNF3 to a linker histone site on the nucleosome. EMBO J. 17, 244–254 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Cirillo, L. A. et al. Opening of compacted chromatin by early developmental transcription factors HNF3 (FoxA) and GATA-4. Mol. Cell 9, 279–289 (2002).

    Article  CAS  PubMed  Google Scholar 

  130. Taube, J. H., Allton, K., Duncan, S. A., Shen, L. & Barton, M. C. Foxa1 functions as a pioneer transcription factor at transposable elements to activate Afp during differentiation of embryonic stem cells. J. Biol. Chem. 285, 16135–16144 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ghosh, R. P., Horowitz-Scherer, R. A., Nikitina, T., Shlyakhtenko, L. S. & Woodcock, C. L. MeCP2 binds cooperatively to its substrate and competes with histone H1 for chromatin binding sites. Mol. Cell. Biol. 30, 4656–4670 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Xu, N., Emelyanov, A. V., Fyodorov, D. V. & Skoultchi, A. I. Drosophila linker histone H1 coordinates STAT-dependent organization of heterochromatin and suppresses tumorigenesis caused by hyperactive JAK-STAT signaling. Epigenetics Chromatin 7, 16 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Kim, K. et al. Isolation and characterization of a novel H1.2 complex that acts as a repressor of p53-mediated transcription. J. Biol. Chem. 283, 9113–9126 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Lee, H., Habas, R. & Abate-Shen, C. MSX1 cooperates with histone H1b for inhibition of transcription and myogenesis. Science 304, 1675–1678 (2004).

    Article  CAS  PubMed  Google Scholar 

  135. Daujat, S., Zeissler, U., Waldmann, T., Happel, N. & Schneider, R. HP1 binds specifically to Lys26-methylated histone H1.4, whereas simultaneous Ser27 phosphorylation blocks HP1 binding. J. Biol. Chem. 280, 38090–38095 (2005).

    Article  CAS  PubMed  Google Scholar 

  136. Nielsen, A. L. et al. Heterochromatin formation in mammalian cells: interaction between histones and HP1 proteins. Mol. Cell 7, 729–739 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. Kavi, H., Emelyanov, A. V., Fyodorov, D. V. & Skoultchi, A. I. Independent biological and biochemical functions for individual structural domains of Drosophila linker histone H1. J. Biol. Chem. 291, 15143–15155 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Lu, X., Hamkalo, B., Parseghian, M. H. & Hansen, J. C. Chromatin condensing functions of the linker histone C-terminal domain are mediated by specific amino acid composition and intrinsic protein disorder. Biochemistry 48, 164–172 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. McBryant, S. J., Lu, X. & Hansen, J. C. Multifunctionality of the linker histones: an emerging role for protein-protein interactions. Cell Res. 20, 519–528 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Starkova, T. Y. et al. Post-translational modifications of linker histone H1 variants in mammals. Phys. Biol. 14, 016005 (2017).

    Article  CAS  PubMed  Google Scholar 

  141. Talasz, H., Helliger, W., Puschendorf, B. & Lindner, H. In vivo phosphorylation of histone H1 variants during the cell cycle. Biochemistry 35, 1761–1767 (1996).

    Article  CAS  PubMed  Google Scholar 

  142. Chu, C. S. et al. Protein kinase A-mediated serine 35 phosphorylation dissociates histone H1.4 from mitotic chromosome. J. Biol. Chem. 286, 35843–35851 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kim, K. et al. Functional interplay between p53 acetylation and H1.2 phosphorylation in p53-regulated transcription. Oncogene 31, 4290–4301 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Talasz, H., Sarg, B. & Lindner, H. H. Site-specifically phosphorylated forms of H1.5 and H1.2 localized at distinct regions of the nucleus are related to different processes during the cell cycle. Chromosoma 118, 693–709 (2009).

    Article  CAS  PubMed  Google Scholar 

  145. Zheng, Y. et al. Histone H1 phosphorylation is associated with transcription by RNA polymerases I and II. J. Cell Biol. 189, 407–415 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Bonet-Costa, C. et al. Combined bottom-up and top-down mass spectrometry analyses of the pattern of post-translational modifications of Drosophila melanogaster linker histone H1. J. Proteomics 75, 4124–4138 (2012).

    Article  CAS  PubMed  Google Scholar 

  147. Kamieniarz, K. et al. A dual role of linker histone H1.4 Lys 34 acetylation in transcriptional activation. Genes Dev. 26, 797–802 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Lesner, A. et al. Monoubiquitinated histone H1B is required for antiviral protection in CD4+T cells resistant to HIV-1. Biochemistry 43, 16203–16211 (2004).

    Article  CAS  PubMed  Google Scholar 

  149. Talbert, P. B. et al. A unified phylogeny-based nomenclature for histone variants. Epigenetics Chromatin 5, 7 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Izzo, A. & Schneider, R. H1 gets the genome in shape. Genome Biol. 17, 8 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors apologize to those colleagues whose works were not cited due to subjects not covered or limitations in the number of references permitted. The authors' work is supported by grants from the U.S. National Institutes of Health/National Institute of General Medical Sciences to D.V.F. (GM074233) and A.I.S. (GM093190 and GM116143) and by the intramural research programme of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (B.-R.Z. and Y.B.)

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Authors and Affiliations

  1. Department of Cell Biology, Albert Einstein College of Medicine, Bronx, 10461, New York, USA

    Dmitry V. Fyodorov & Arthur I. Skoultchi

  2. Laboratory of Biochemistry and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Bing-Rui Zhou & Yawen Bai

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  1. Dmitry V. Fyodorov
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  2. Bing-Rui Zhou
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  3. Arthur I. Skoultchi
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All authors contributed equally to researching data for the article, discussion of content and writing and reviewing of the manuscript before submission.

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Correspondence to Dmitry V. Fyodorov or Yawen Bai.

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Glossary

Winged helix fold

A compact structural motif in proteins consisting of three α-helices and two or three β-strands and a loop (wing) between the last two β-strands.

Histone chaperones

A group of proteins that bind histones and regulate nucleosome assembly, initially coined to describe the function of nucleoplasmin in the prevention of histone–DNA aggregation during nucleosome assembly.

Citrullination

The conversion of the amino acid arginine in a protein into the amino acid citrulline by deimination.

Facultative heterochromatin

A chromatin region in which genes are silenced through a mechanism such as histone methylation or PIWI-interacting RNA (piRNA).

Nucleosome dyad

The middle point of the DNA that is on the two-fold symmetry axis in the nucleosome core particle structure.

Stochastic optical reconstruction microscopy

(STORM). A form of light microscopy where nearby fluorophores are excited individually, which allows reconstruction of images with resolution beyond the diffraction limit of light.

DNA hypersensitivity sites

(DHSs). Regions of chromatin that are sensitive to cleavage by DNase I enzymes.

DNA adenine methyltransferase identification

(DamID). Molecular protocol used to map binding sites of DNA-associated factors in eukaryotes. The DNA-binding factor is fused with a prokaryotic DNA methyltransferase and expressed in vivo; the fusion protein labels DNA in the vicinity of binding sites with a non-naturally occurring methyl-A.

Histone code

A hypothesis that certain functions of the genome are governed by recognition of combinatorial chemical modifications of histones.

Polytene chromosomes

Oversized chromosomes resulting from chromatin expansion due to polyploidization found in the salivary glands of Drosophila melanogaster.

Transposable elements

Also known as transposons. Segments of DNA that can change their location in the genome.

PIWI proteins

A class of regulatory proteins responsible for maintaining incomplete differentiation in stem cells and maintaining the stability of cell division rates in germline cells.

Heterochromatin protein 1

(HP1). A family of proteins associated with heterochromatin structure formation and maintenance. The HP1 family includes several isoforms (HP1α, HP1β, etc.).

Imprinting

An epigenetic phenomenon in which specific genes are expressed only from DNA inherited from one of the parents, owing to silencing of the chromatin in the other parental genome.

Homeobox gene cluster

A cluster of a large family of similar genes that direct the formation of many body structures during early embryonic development.

Endoreplication

Replication of the nuclear genome in the absence of cell division, which leads to elevated nuclear gene content and polyploidy.

Intercalary heterochromatin

Heterochromatin, other than centromeric heterochromatin, dispersed throughout eukaryotic chromosomes.

Imaginal disc

One of the parts of a holometabolous insect larva that will become a portion of the outside of the adult insect (for example, a wing) during the larval to pupal transition (metamorphosis).

V(D)J recombination

Unique mechanism of somatic DNA recombination that occurs in developing B and T cells to give rise to a diverse repertoire of immunoglobulins.

Cryptic promoters

Genomic sequences in eukaryotes that may be intermittently utilized for transcription initiation; core promoter elements of cryptic promoters are poorly defined (do not strongly interact with general transcription factors) and are obstructed by nucleosome structure and thus silenced in normal cells.

Poly(ADP-ribose) polymerase 1

(PARP1). A nuclear enzyme in eukaryotes that post-translationally modifies proteins by poly ADP-ribosylation.

Retinoic acid

Metabolite of vitamin A (retinol) and a ligand for the retinoic acid receptor transcription factor, an essential intercellular signalling molecule that guides anterior–posterior patterning during early development of chordate animals.

JAK–STAT signalling

Extracellular chemical signalling pathway that regulates the transcription of multiple genes involved in proliferation, differentiation, immunity, and others. The signalling cascade involves Janus kinase (JAK) cell surface receptors and signal transducers and activators of transcription (STATs).

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Fyodorov, D., Zhou, BR., Skoultchi, A. et al. Emerging roles of linker histones in regulating chromatin structure and function. Nat Rev Mol Cell Biol 19, 192–206 (2018). https://doi.org/10.1038/nrm.2017.94

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