The Effect of Oncomutations and Posttranslational Modifications of Histone H1 on Chromatosome Structure and Stability

  • M. V. Bass
  • G. A. Armeev
  • K. V. Shaitan
  • A. K. ShaytanEmail author


The stability of chromatosome when introducing posttranslational modifications and mutations observed in the case of oncological diseases into the structure of the linker histone was studied using bioinformatics analysis. The chromatosome is formed under the interaction of the nucleosome with the linker histone. This interaction can be characterized by the binding free energy. We hypothesized that oncomutations and posttranslational modifications of the linker histone are associated with a change in its free energy of binding to the nucleosome, and it probably leads to a change in chromatin compaction, thus affecting gene expression. Calculations of the binding free energy were performed using algorithms of the FoldX program. Screening of positions of posttranslational modifications in the linker histone for the presence of steric constraints was also performed. The analysis of the obtained data allowed for the identification of oncomutations and posttranslational modifications that significantly change the binding free energy of the linker histone with the nucleosome, thereby probably affecting the structure of the entire chromatin.


nucleosome chromatin free energy DNA histones mutations posttranslational modifications. 



This work was financially supported by the Russian Science Foundation (project no. 19-74-30003).


Conflict of interest. The authors declare that they do not have any conflict of interest.

Statement on the welfare of animals. This article does not contain any studies involving animals performed by any of the authors.

Statement of compliance with standards of research involving humans as subjects. This article does not contain any studies involving humans as subjects of research.


  1. 1.
    Zhou, B.-R., Jiang, J., Feng, H., Ghirlando, R., Xiao, T.S., and Bai, Y., Structural mechanisms of nucleosome recognition by linker histones, Mol. Cell, 2015, vol. 59, no. 4, pp. 628–638.CrossRefGoogle Scholar
  2. 2.
    Bednar, J., Garcia-Saez, I., Boopathi, R., et al., Structure and dynamics of a 197 bp nucleosome in complex with linker histone H1, Mol. Cell, 2017, vol. 66, no. 3, pp. 384–397.CrossRefGoogle Scholar
  3. 3.
    Gorkovets, T.K., Armeev, G.A., Shaitan, K.V., and Shaytan, A.K., Joint effect of histone H1 amino acid sequence and DNA nucleotide sequence on the structure of chromatosomes: Analysis by molecular modeling methods, Moscow Univ. Biol. Sci. Bull., 2018, vol. 73, no. 2, pp. 82–87.CrossRefGoogle Scholar
  4. 4.
    Draizen, E.J., Shaytan, A.K., Mariño-Ramírez, L., Talbert, P.B., Landsman, D., and Panchenko, A.R., HistoneDB 2.0: A histone database with variants—an integrated resource to explore histones and their variants, Database (Oxford), 2016, vol. 2016. CrossRefGoogle Scholar
  5. 5.
    Kuzmichev, A., Jenuwein, T., Tempst, P., and Reinberg, D., Different Ezh2-containing complexes target methylation of histone H1 or nucleosomal histone H3, Mol. Cell, 2004, vol. 14, no. 2, pp. 183–193.CrossRefGoogle Scholar
  6. 6.
    Th'ng, J.P.H., Sung, R., Ye, M., and Hendzel, M.J., H1 family histones in the nucleus. Control of binding and localization by the C-terminal domain, J. Biol. Chem., 2005, vol. 280, no. 30, pp. 27809–27814.CrossRefGoogle Scholar
  7. 7.
    Li, H., Kaminski, M.S., Li, Y., 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, 2014, vol. 123, no. 10, pp. 1487–1498.CrossRefGoogle Scholar
  8. 8.
    Tatton-Brown, K., Loveday, C., Yost, S., et al., Mutations in epigenetic regulation genes are a major cause of overgrowth with intellectual disability, Am. J. Hum. Genet., 2017, vol. 100, no. 5, pp. 725–736.CrossRefGoogle Scholar
  9. 9.
    Sjöblom, T., Jones, S., Wood, L.D., et al., The consensus coding sequences of human breast and colorectal cancers, Science, 2006, vol. 314, no. 5797, pp. 268–274.CrossRefGoogle Scholar
  10. 10.
    Th'ng, J.P., Guo, X.W., Swank, R.A., Crissman, H.A., and Bradbury, E.M., Inhibition of histone phosphorylation by staurosporine leads to chromosome decondensation, J. Biol. Chem., 1994, vol. 269, no. 13, pp. 9568–9573.PubMedGoogle Scholar
  11. 11.
    Clausell, J., Happel, N., Hale, T.K., Doenecke, D., and Beato, M., Histone H1 subtypes differentially modulate chromatin condensation without preventing ATP-dependent remodeling by SWI/SNF or NURF, PLoS One, 2009, vol. 4, no. 10, e0007243.CrossRefGoogle Scholar
  12. 12.
    Christophorou, M.A., Castelo-Branco, G., Halley-Stott, R.P., Oliveira, C.S., Loos, R., Radzisheuskaya, A., Mowen, K.A., Bertone, P., Silva, J.C.R., Zernicka-Goetz, M., Nielsen, M.L., Gurdon, J.B., and Kouzarides, T., Citrullination regulates pluripotency and histone H1 binding to chromatin, Nature, 2014, vol. 507, no. 7490, pp. 104–108.CrossRefGoogle Scholar
  13. 13.
    Dai, L., Peng, C., Montellier, E., et al., Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark, Nat. Chem. Biol., 2014, vol. 10, no. 5, pp. 365–370.CrossRefGoogle Scholar
  14. 14.
    Xie, Z., Zhang, D., Chung, D., et al., Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation, Mol. Cell, 2016, vol. 62, no. 2, pp. 194–206.CrossRefGoogle Scholar
  15. 15.
    Nacev, B.A., Feng, L., Bagert, J.D., Lemiesz, A.E., Gao, J., Soshnev, A.A., Kundra, R., Schultz, N., Muir, T.W., and Allis, C.D., The expanding landscape of “oncohistone” mutations in human cancers, Nature, 2019, vol. 567, no. 7749, p. 473.CrossRefGoogle Scholar
  16. 16.
    Webb, B. and Sali, A., Protein structure modeling with MODELLER, in Protein Structure Prediction. Methods in Molecular Biology (Methods and Protocols), Kihara, D., Ed., New York: Humana Press, 2014, pp. 1–15.Google Scholar
  17. 17.
    Schymkowitz, J., Borg, J., Stricher, F., Nys, R., Rousseau, F., and Serrano, L., The FoldX web server: An online force field, Nucleic Acid Res., 2005, vol. 33, suppl. 2, pp. W382–W388.CrossRefGoogle Scholar
  18. 18.
    Tate, J.G., Bamford, S., Jubb, H.C., et al., COSMIC: The catalogue of somatic mutations in cancer, Nucleic Acid Res., 2019, vol. 47, no. D1, pp. D941–D947.CrossRefGoogle Scholar
  19. 19.
    Adzhubei, I.A., Schmidt, S., Peshkin, L., Ramensky, V.E., Gerasimova, A., Bork, P., Kondrashov, A.S., and Sunyaev, S.R., A method and server for predicting damaging missense mutations, Nature Methods, 2010, vol. 7, no. 4, pp. 248–249.CrossRefGoogle Scholar
  20. 20.
    UniProt: A worldwide hub of protein knowledge, Nucleic Acids Res., 2019, vol. 47, no. D1, pp. D506–D515.Google Scholar
  21. 21.
    Margreitter, C., Petrov, D., and Zagrovic, B., Vienna-PTM web server: A toolkit for MD simulations of protein post-translational modifications, Nucleic Acid Res., 2013, vol. 41, no. W1, pp. W422–W426.CrossRefGoogle Scholar
  22. 22.
    Hanwell, M.D., Curtis, D.E., Lonie, D.C., Vandermeersch, T., Zurek, E., and Hutchison, G.R., Avogadro: An advanced semantic chemical editor, visualization, and analysis platform, J. Cheminf., 2012, vol. 4, p. 17.CrossRefGoogle Scholar
  23. 23.
    Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenblatt, D.M., Meng, E.C., and Ferrin, T.E., UCSF chimera—a visualization system for exploratory research and analysis, J. Comput. Chem., 2004, vol. 25, no. 13, pp. 1605–1612.CrossRefGoogle Scholar
  24. 24.
    Bozic, I., Antal, T., Ohtsuki, H., Carter, H., Kim, D., Chen, S., Karchin, R., Kinzler, K.W., Vogelstein, B., and Nowak, M.A., Accumulation of driver and passenger mutations during tumor progression, Proc. Natl. Acad. Sci. U.S.A., 2010, vol. 107, no. 43, pp. 18545–18550.CrossRefGoogle Scholar
  25. 25.
    Schwartzentruber, J., Korshunov, A., Liu, X.Y., et al., Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma, Nature, 2012, vol. 482, no. 7384, pp. 226–231.CrossRefGoogle Scholar
  26. 26.
    Kumar, N.M. and Walker, I.O., The binding of histones H1 and H5 to chromatin in chicken erythrocyte nuclei, Nucleic Acid Res., 1980, vol. 8, no. 16, pp. 3535–3552.CrossRefGoogle Scholar

Copyright information

© Allerton Press, Inc. 2019

Authors and Affiliations

  • M. V. Bass
    • 1
  • G. A. Armeev
    • 1
  • K. V. Shaitan
    • 1
  • A. K. Shaytan
    • 1
    Email author
  1. 1.Department of Biology, Moscow State UniversityMoscowRussia

Personalised recommendations