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.

  • Perspective
  • Published:

Scratching the (lateral) surface of chromatin regulation by histone modifications

Nature Structural & Molecular Biology volume 20, pages 657–661 (2013)Cite this article

Subjects

Abstract

Histones have two structurally and functionally distinct domains: globular domains forming the nucleosomal core around which DNA is wrapped and unstructured tails protruding from the nucleosomal core. Whereas post-translational modifications (PTMs) in histone tails are well studied, much less is currently known about histone-core PTMs. Many core PTMs map to residues located on the lateral surface of the histone octamer, close to the DNA, and they have the potential to alter intranucleosomal histone-DNA interactions. Here we discuss recent advances in understanding the function of lateral-surface PTMs. Whereas modifications in the histone tails might have limited structural impact on the nucleosome itself and function as signals to recruit specific binding proteins, PTMs in the lateral surface can have a direct structural effect on nucleosome and chromatin dynamics, even in the absence of specific binding proteins, which adds a twist to the debate on the functionality and causality of PTMs.

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: Modifications in the histone tail and the globular histone domain.
Figure 2: Post-translational modifications of the lateral surface can have different effects on nucleosome dynamics, depending on their localization (model based on PDB 1KX5; tails have been omitted for visibility).

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Luger, K., Mäder, 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).

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  3. Freitas, M.A., Sklenar, A.R. & Parthun, M.R. Application of mass spectrometry to the identification and quantification of histone post-translational modifications. J. Cell. Biochem. 92, 691–700 (2004).

    Article  CAS  Google Scholar 

  4. Cosgrove, M.S., Boeke, J.D. & Wolberger, C. Regulated nucleosome mobility and the histone code. Nat. Struct. Mol. Biol. 11, 1037–1043 (2004).

    Article  CAS  Google Scholar 

  5. Cosgrove, M.S. Histone proteomics and the epigenetic regulation of nucleosome mobility. Expert Rev. Proteomics 4, 465–478 (2007).

    Article  CAS  Google Scholar 

  6. Cohen, I., Poreba, E., Kamieniarz, K. & Schneider, R. Histone modifiers in cancer: friends or foes? Genes Cancer 2, 631–647 (2011).

    Article  CAS  Google Scholar 

  7. Bannister, A.J. & Kouzarides, T. Regulation of chromatin by histone modifications. Cell Res. 21, 381–395 (2011).

    Article  CAS  Google Scholar 

  8. Zhou, V.W., Goren, A. & Bernstein, B.E. Charting histone modifications and the functional organization of mammalian genomes. Nat. Rev. Genet. 12, 7–18 (2010).

    Article  Google Scholar 

  9. Chi, P., Allis, C.D. & Wang, G.G. Covalent histone modifications—miswritten, misinterpreted and mis-erased in human cancers. Nat. Rev. Cancer 10, 457–469 (2010).

    Article  CAS  Google Scholar 

  10. Ausio, J., Dong, F. & van Holde, K.E. Use of selectively trypsinized nucleosome core particles to analyze the role of the histone “tails” in the stabilization of the nucleosome. J. Mol. Biol. 206, 451–463 (1989).

    Article  CAS  Google Scholar 

  11. Li, G. & Reinberg, D. Chromatin higher-order structures and gene regulation. Curr. Opin. Genet. Dev. 21, 175–186 (2011).

    Article  CAS  Google Scholar 

  12. Taverna, S.D., Li, H., Ruthenburg, A.J., Allis, C.D. & Patel, D.J. How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat. Struct. Mol. Biol. 14, 1025–1040 (2007).

    Article  CAS  Google Scholar 

  13. Musselman, C.A., Lalonde, M.E., Cote, J. & Kutateladze, T.G. Perceiving the epigenetic landscape through histone readers. Nat. Struct. Mol. Biol. 19, 1218–1227 (2012).

    Article  CAS  Google Scholar 

  14. Shilatifard, A. Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation. Curr. Opin. Cell Biol. 20, 341–348 (2008).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  16. Pengelly, A.R., Copur, O., Jackle, H., Herzig, A. & Muller, J. A histone mutant reproduces the phenotype caused by loss of histone-modifying factor Polycomb. Science 339, 698–699 (2013).

    Article  CAS  Google Scholar 

  17. Henikoff, S. & Shilatifard, A. Histone modification: cause or cog? Trends Genet. 27, 389–396 (2011).

    Article  CAS  Google Scholar 

  18. Turner, B.M. The adjustable nucleosome: an epigenetic signaling module. Trends Genet. 28, 436–444 (2012).

    Article  CAS  Google Scholar 

  19. Anderson, J.D., Thastrom, A. & Widom, J. Spontaneous access of proteins to buried nucleosomal DNA target sites occurs via a mechanism that is distinct from nucleosome translocation. Mol. Cell Biol. 22, 7147–7157 (2002).

    Article  CAS  Google Scholar 

  20. Li, G., Levitus, M., Bustamante, C. & Widom, J. Rapid spontaneous accessibility of nucleosomal DNA. Nat. Struct. Mol. Biol. 12, 46–53 (2005).

    Article  CAS  Google Scholar 

  21. North, J.A. et al. Regulation of the nucleosome unwrapping rate controls DNA accessibility. Nucleic Acids Res. 40, 10215–10227 (2012).

    Article  CAS  Google Scholar 

  22. Dai, J. et al. Probing nucleosome function: a highly versatile library of synthetic histone H3 and H4 mutants. Cell 134, 1066–1078 (2008).

    Article  CAS  Google Scholar 

  23. Hyland, E.M. et al. Insights into the role of histone H3 and histone H4 core modifiable residues in Saccharomyces cerevisiae. Mol. Cell Biol. 25, 10060–10070 (2005).

    Article  CAS  Google Scholar 

  24. Fenley, A.T., Adams, D.A. & Onufriev, A.V. Charge state of the globular histone core controls stability of the nucleosome. Biophys. J. 99, 1577–1585 (2010).

    Article  CAS  Google Scholar 

  25. Chatterjee, C. & Muir, T.W. Chemical approaches for studying histone modifications. J. Biol. Chem. 285, 11045–11050 (2010).

    Article  CAS  Google Scholar 

  26. Tropberger, P. & Schneider, R. Going global: novel histone modifications in the globular domain of H3. Epigenetics 5, 112–117 (2010).

    Article  CAS  Google Scholar 

  27. Neumann, H. et al. A method for genetically installing site-specific acetylation in recombinant histones defines the effects of H3 K56 acetylation. Mol. Cell 36, 153–163 (2009).

    Article  CAS  Google Scholar 

  28. Simon, M. et al. Histone fold modifications control nucleosome unwrapping and disassembly. Proc. Natl. Acad. Sci. USA 108, 12711–12716 (2011).

    Article  CAS  Google Scholar 

  29. Shimko, J.C., North, J.A., Bruns, A.N., Poirier, M.G. & Ottesen, J.J. Preparation of fully synthetic histone H3 reveals that acetyl-lysine 56 facilitates protein binding within nucleosomes. J. Mol. Biol. 408, 187–204 (2011).

    Article  CAS  Google Scholar 

  30. Almer, A., Rudolph, H., Hinnen, A. & Horz, W. Removal of positioned nucleosomes from the yeast PHO5 promoter upon PHO5 induction releases additional upstream activating DNA elements. EMBO J. 5, 2689–2696 (1986).

    Article  CAS  Google Scholar 

  31. Lam, F.H., Steger, D.J. & O'Shea, E.K. Chromatin decouples promoter threshold from dynamic range. Nature 453, 246–250 (2008).

    Article  CAS  Google Scholar 

  32. Williams, S.K., Truong, D. & Tyler, J.K. Acetylation in the globular core of histone H3 on lysine-56 promotes chromatin disassembly during transcriptional activation. Proc. Natl. Acad. Sci. USA 105, 9000–9005 (2008).

    Article  CAS  Google Scholar 

  33. Li, Q. et al. Acetylation of histone H3 lysine 56 regulates replication-coupled nucleosome assembly. Cell 134, 244–255 (2008).

    Article  CAS  Google Scholar 

  34. Chen, C.C. et al. Acetylated lysine 56 on histone H3 drives chromatin assembly after repair and signals for the completion of repair. Cell 134, 231–243 (2008).

    Article  CAS  Google Scholar 

  35. Vempati, R.K. et al. p300-mediated acetylation of histone H3 lysine 56 functions in DNA damage response in mammals. J. Biol. Chem. 285, 28553–28564 (2010).

    Article  CAS  Google Scholar 

  36. Xie, W. et al. Histone H3 lysine 56 acetylation is linked to the core transcriptional network in human embryonic stem cells. Mol. Cell 33, 417–427 (2009).

    Article  CAS  Google Scholar 

  37. Das, C., Lucia, M.S., Hansen, K.C. & Tyler, J.K. CBP/p300-mediated acetylation of histone H3 on lysine 56. Nature 459, 113–117 (2009).

    Article  CAS  Google Scholar 

  38. Drogaris, P. et al. Histone deacetylase inhibitors globally enhance H3/H4 tail acetylation without affecting H3 lysine 56 acetylation. Sci. Rep. 2, 220 (2012).

    Article  Google Scholar 

  39. Garcia, B.A. et al. Organismal differences in post-translational modifications in histones H3 and H4. J. Biol. Chem. 282, 7641–7655 (2007).

    Article  CAS  Google Scholar 

  40. Daujat, S. et al. H3K64 trimethylation marks heterochromatin and is dynamically remodeled during developmental reprogramming. Nat. Struct. Mol. Biol. 16, 777–781 (2009).

    Article  CAS  Google Scholar 

  41. Zhang, L., Eugeni, E.E., Parthun, M.R. & Freitas, M.A. Identification of novel histone post-translational modifications by peptide mass fingerprinting. Chromosoma 112, 77–86 (2003).

    Article  CAS  Google Scholar 

  42. North, J.A. et al. Phosphorylation of histone H3(T118) alters nucleosome dynamics and remodeling. Nucleic Acids Res. 39, 6465–6474 (2011).

    Article  CAS  Google Scholar 

  43. Muthurajan, U.M. et al. Crystal structures of histone Sin mutant nucleosomes reveal altered protein-DNA interactions. EMBO J. 23, 260–271 (2004).

    Article  CAS  Google Scholar 

  44. Kurumizaka, H. & Wolffe, A.P. Sin mutations of histone H3: influence on nucleosome core structure and function. Mol. Cell Biol. 17, 6953–6969 (1997).

    Article  CAS  Google Scholar 

  45. Kruger, W. et al. Amino acid substitutions in the structured domains of histones H3 and H4 partially relieve the requirement of the yeast SWI/SNF complex for transcription. Genes Dev. 9, 2770–2779 (1995).

    Article  CAS  Google Scholar 

  46. Bintu, L. et al. Nucleosomal elements that control the topography of the barrier to transcription. Cell 151, 738–749 (2012).

    Article  CAS  Google Scholar 

  47. Manohar, M. et al. Acetylation of histone H3 at the nucleosome dyad alters DNA-histone binding. J. Biol. Chem. 284, 23312–23321 (2009).

    Article  CAS  Google Scholar 

  48. Tropberger, P. et al. Regulation of transcription through acetylation of H3K122 on the lateral surface of the histone octamer. Cell 152, 859–872 (2013).

    Article  CAS  Google Scholar 

  49. Tweedie-Cullen, R.Y. et al. Identification of combinatorial patterns of post-translational modifications on individual histones in the mouse brain. PLoS ONE 7, e36980 (2012).

    Article  CAS  Google Scholar 

  50. Tan, M. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1016–1028 (2011).

    Article  CAS  Google Scholar 

  51. English, C.M., Maluf, N.K., Tripet, B., Churchill, M.E.A. & Tyler, J.K. ASF1 binds to a heterodimer of histones H3 and H4: a two-step mechanism for the assembly of the H3–H4 heterotetramer on DNA. Biochemistry 44, 13673–13682 (2005).

    Article  CAS  Google Scholar 

  52. Xie, Z. et al. Lysine succinylation and lysine malonylation in histones. Mol. Cell Proteomics 11, 100–107 (2012).

    Article  CAS  Google Scholar 

  53. Javaid, S. et al. Nucleosome remodeling by hMSH2-hMSH6. Mol. Cell 36, 1086–1094 (2009).

    Article  CAS  Google Scholar 

  54. Ransom, M., Dennehey, B.K. & Tyler, J.K. Chaperoning histones during DNA replication and repair. Cell 140, 183–195 (2010).

    Article  CAS  Google Scholar 

  55. De Koning, L., Corpet, A., Haber, J.E. & Almouzni, G. Histone chaperones: an escort network regulating histone traffic. Nat. Struct. Mol. Biol. 14, 997–1007 (2007).

    Article  CAS  Google Scholar 

  56. Kang, B. et al. Phosphorylation of H4 Ser 47 promotes HIRA-mediated nucleosome assembly. Genes Dev. 25, 1359–1364 (2011).

    Article  CAS  Google Scholar 

  57. Yu, Y. et al. Histone H3 lysine 56 methylation regulates DNA replication through its interaction with PCNA. Mol. Cell 46, 7–17 (2012).

    Article  CAS  Google Scholar 

  58. Gautier, A. et al. Genetically encoded photocontrol of protein localization in mammalian cells. J. Am. Chem. Soc. 132, 4086–4088 (2010).

    Article  CAS  Google Scholar 

  59. Bianco, A., Townsley, F.M., Greiss, S., Lang, K. & Chin, J.W. Expanding the genetic code of Drosophila melanogaster. Nat. Chem. Biol. 8, 748–750 (2012).

    Article  CAS  Google Scholar 

  60. Dawson, M.A. et al. JAK2 phosphorylates histone H3Y41 and excludes HP1α from chromatin. Nature 461, 819–822 (2009).

    Article  CAS  Google Scholar 

  61. Hurd, P.J. et al. Phosphorylation of histone H3 Thr-45 is linked to apoptosis. J. Biol. Chem. 284, 16575–16583 (2009).

    Article  CAS  Google Scholar 

  62. Ferreira, H., Somers, J., Webster, R., Flaus, A. & Owen-Hughes, T. Histone tails and the H3 αN helix regulate nucleosome mobility and stability. Mol. Cell Biol. 27, 4037–4048 (2007).

    Article  CAS  Google Scholar 

  63. Baker, S.P. et al. Histone H3 Thr 45 phosphorylation is a replication-associated post-translational modification in S. cerevisiae. Nat. Cell Biol. 12, 294–298 (2010).

    Article  CAS  Google Scholar 

  64. Xu, F., Zhang, K. & Grunstein, M. Acetylation in histone H3 globular domain regulates gene expression in yeast. Cell 121, 375–385 (2005).

    Article  CAS  Google Scholar 

  65. English, C.M., Adkins, M., Carson, J., Churchill, M. & Tyler, J. Structural basis for the histone chaperone activity of Asf1. Cell 127, 495–508 (2006).

    Article  CAS  Google Scholar 

  66. Williams, S.K., Truong, D. & Tyler, J.K. Acetylation in the globular core of histone H3 on lysine-56 promotes chromatin disassembly during transcriptional activation. Proc. Natl. Acad. Sci. USA 105, 9000–9005 (2008).

    Article  CAS  Google Scholar 

  67. Yuan, J., Pu, M., Zhang, Z. & Lou, Z. Histone H3–K56 acetylation is important for genomic stability in mammals. Cell Cycle 8, 1747–1753 (2009).

    Article  CAS  Google Scholar 

  68. Vempati, R.K. DNA damage in the presence of chemical genotoxic agents induce acetylation of H3K56 and H4K16 but not H3K9 in mammalian cells. Mol. Biol. Rep. 39, 303–308 (2012).

    Article  CAS  Google Scholar 

  69. Xie, W. et al. Histone H3 lysine 56 acetylation is linked to the core transcriptional network in human embryonic stem cells. Mol. Cell 33, 417–427 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  71. Hsieh, F.K., Fisher, M., Ujvari, A., Studitsky, V.M. & Luse, D.S. Histone Sin mutations promote nucleosome traversal and histone displacement by RNA polymerase II. EMBO Rep. 11, 705–710 (2010).

    Article  CAS  Google Scholar 

  72. Hainer, S.J. & Martens, J.A. Identification of histone mutants that are defective for transcription-coupled nucleosome occupancy. Mol. Cell Biol. 31, 3557–3568 (2011).

    Article  CAS  Google Scholar 

  73. Beck, H.C. et al. Quantitative proteomic analysis of post-translational modifications of human histones. Mol. Cell Proteomics 5, 1314–1325 (2006).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank P. Bheda and S. Daujat for critical reading of the manuscript and stimulating discussions as well as all members of the Schneider laboratory. Work in the Schneider laboratory was supported by the Deutsche Forschungs Gemeinschaft (through SFB 746), the Fondation pour la Recherche Medicale and an European Research Council starting grant. We apologize to the authors of all the work that we could not cite owing to space restrictions.

Author information

Authors and Affiliations

  1. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany

    Philipp Tropberger

  2. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104, INSERM U 964, Université de Strasbourg, Illkirch, France

    Philipp Tropberger & Robert Schneider

Authors
  1. Philipp Tropberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert Schneider.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tropberger, P., Schneider, R. Scratching the (lateral) surface of chromatin regulation by histone modifications. Nat Struct Mol Biol 20, 657–661 (2013). https://doi.org/10.1038/nsmb.2581

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nsmb.2581

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