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.

The winding path of protein methylation research: milestones and new frontiers

Abstract

In 1959, while analysing the bacterial flagellar proteins, Ambler and Rees observed an unknown species of amino acid that they eventually identified as methylated lysine. Over half a century later, protein methylation is known to have a regulatory role in many essential cellular processes that range from gene transcription to signal transduction. However, the road to this now burgeoning research field was obstacle-ridden, not least because of the inconspicuous nature of the methyl mark itself. Here, we chronicle the milestone achievements and discuss the future of protein methylation research.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Milestones in protein methylation research.
Figure 2: Interfaces between protein methylation and biological processes.
Figure 3: Protein methylation in numbers.

References

  1. Ambler, R. P. & Rees, M. W. Epsilon-N-methyl-lysine in bacterial flagellar protein. Nature 184, 56–57 (1959).

    Article  CAS  PubMed  Google Scholar 

  2. Neuberger, A. & Sanger, F. The availability of in-acetyl-d-lysine and in-methyl-dl-lysine for growth. Biochem. J. 38, 125–129 (1944).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Neuberger, A. & Sanger, F. The metabolism of lysine. Biochem. J. 38, 119–125 (1944).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Stocker, B. & McDonough, M. A gene determining presence or absence of ɛ-N-methyl-lysine in Salmonella flagellar protein. Nature 189, 556–558 (1961).

    Article  Google Scholar 

  5. Murray, K. The occurrence of epsilon-N-methyl lysine in histones. Biochemistry 3, 10–15 (1964).

    Article  CAS  PubMed  Google Scholar 

  6. Allfrey, V. G., Faulkner, R. & Mirsky, A. E. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc. Natl Acad. Sci. USA 51, 786–794 (1964).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kim, S. & Paik, W. K. Studies on the origin of epsilon-N-methyl-L-lysine in protein. J. Biol. Chem. 240, 4629–4634 (1965).

    Article  CAS  PubMed  Google Scholar 

  8. Fischer, E. H., Graves, D. J., Crittenden, E. R. & Krebs, E. G. Structure of the site phosphorylated in the phosphorylase b to a reaction. J. Biol. Chem. 234, 1698–1704 (1959).

    Article  CAS  PubMed  Google Scholar 

  9. Phillips, D. M. The presence of acetyl groups of histones. Biochem. J. 87, 258–263 (1963).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Walsh, D. A., Perkins, J. P. & Krebs, E. G. An adenosine 3′,5′-monophosphate-dependant protein kinase from rabbit skeletal muscle. J. Biol. Chem. 243, 3763–3765 (1968).

    Article  CAS  PubMed  Google Scholar 

  11. Burnett, G. & Kennedy, E. P. The enzymatic phosphorylation of proteins. J. Biol. Chem. 211, 969–980 (1954).

    Article  CAS  PubMed  Google Scholar 

  12. Paik, W. K. & Kim, S. Protein methylase I. Purification and properties of the enzyme. J. Biol. Chem. 243, 2108–2114 (1968).

    Article  CAS  PubMed  Google Scholar 

  13. Paik, W. K. & Kim, S. Solubilization and partial purification of protein methylase 3 from calf thymus nuclei. J. Biol. Chem. 245, 6010–6015 (1970).

    Article  CAS  PubMed  Google Scholar 

  14. Liss, M. & Edelstein, L. M. Evidence for the enzymatic methylation of crystalline ovalbumin preparations. Biochem. Biophys. Res. Commun. 26, 497–504 (1967).

    Article  CAS  PubMed  Google Scholar 

  15. Hempel, K. & Lange, H. W. Nɛ-methylated lysine in histones from chicken erythrocytes. Hoppe-Seyler's Z. Physiol. Chem. 349, 603–607 (in German) (1968).

    Article  CAS  Google Scholar 

  16. Baldwin, G. S. & Carnegie, P. R. Specific enzymic methylation of an arginine in the experimental allergic encephalomyelitis protein from human myelin. Science 171, 579–581 (1971).

    Article  CAS  PubMed  Google Scholar 

  17. Brostoff, S. & Eylar, E. H. Localization of methylated arginine in the A1 protein from myelin. Proc. Natl Acad. Sci. USA 68, 765–769 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kakimoto, Y. & Akazawa, S. Isolation and identification of NG,NG- and NG,NG-dimethyl-arginine, Nɛ-mono-, di-, and trimethyllysine, and glucosylgalactosyl- and galactosyl-δ-hydroxylysine from human urine. J. Biol. Chem. 245, 5751–5758 (1970).

    Article  CAS  PubMed  Google Scholar 

  19. Kim, S., Benoiton, L. & Paik, W. K. Epsilon-alkyllysinase, purification and properties of the enzyme. J. Biol. Chem. 239, 3790–3796 (1964).

    Article  CAS  PubMed  Google Scholar 

  20. Paik, W. K. & Kim, S. Enzymatic demethylation of calf thymus histones. Biochem. Biophys. Res. Commun. 51, 781–788 (1973).

    Article  CAS  PubMed  Google Scholar 

  21. Duerre, J. A. & Lee, C. T. In vivo methylation and turnover of rat brain histones. J. Neurochem. 23, 541–547 (1974).

    Article  CAS  PubMed  Google Scholar 

  22. Byvoet, P., Shepherd, G. R., Hardin, J. M. & Noland, B. J. The distribution and turnover of labeled methyl groups in histone fractions of cultured mammalian cells. Arch. Biochem. Biophys. 148, 558–567 (1972).

    Article  CAS  PubMed  Google Scholar 

  23. Stallcup, M. R. Role of protein methylation in chromatin remodeling and transcriptional regulation. Oncogene 20, 3014–3020 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Calnan, B. J., Tidor, B., Biancalana, S., Hudson, D. & Frankel, A. D. Arginine-mediated RNA recognition: the arginine fork. Science 252, 1167–1171 (1991).

    Article  CAS  PubMed  Google Scholar 

  25. Najbauer, J., Johnson, B. A., Young, A. L. & Aswad, D. W. Peptides with sequences similar to glycine, arginine-rich motifs in proteins interacting with RNA are efficiently recognized by methyltransferase(s) modifying arginine in numerous proteins. J. Biol. Chem. 268, 10501–10509 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Clarke, S. Protein methylation. Curr. Opin. Cell Biol. 5, 977–983 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. Orlando, V. Mapping chromosomal proteins in vivo by formaldehyde-crosslinked-chromatin immunoprecipitation. Trends Biochem. Sci. 25, 99–104 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Solomon, M. J., Larsen, P. L. & Varshavsky, A. Mapping protein-DNA interactions in vivo with formaldehyde: evidence that histone H4 is retained on a highly transcribed gene. Cell 53, 937–947 (1988).

    Article  CAS  PubMed  Google Scholar 

  29. Brownell, J. E. et al. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell 84, 843–851 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Taunton, J., Hassig, C. A. & Schreiber, S. L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272, 408–411 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Klein, R. R. & Houtz, R. L. Cloning and developmental expression of pea ribulose-1,5-bisphosphate carboxylase/oxygenase large subunit N-methyltransferase. Plant Mol. Biol. 27, 249–261 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Henry, M. F. & Silver, P. A. A novel methyltransferase (Hmt1p) modifies poly(A)+-RNA-binding proteins. Mol. Cell. Biol. 16, 3668–3678 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lin, W. J., Gary, J. D., Yang, M. C., Clarke, S. & Herschman, H. R. The mammalian immediate-early TIS21 protein and the leukemia-associated BTG1 protein interact with a protein-arginine N-methyltransferase. J. Biol. Chem. 271, 15034–15044 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Shen, E. C. et al. Arginine methylation facilitates the nuclear export of hnRNP proteins. Genes Dev. 12, 679–691 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chen, D. et al. Regulation of transcription by a protein methyltransferase. Science 284, 2174–2177 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Strahl, B. D., Ohba, R., Cook, R. G. & Allis, C. D. Methylation of histone H3 at lysine 4 is highly conserved and correlates with transcriptionally active nuclei in Tetrahymena. Proc. Natl Acad. Sci. USA 96, 14967–14972 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Herz, H. M., Garruss, A. & Shilatifard, A. SET for life: biochemical activities and biological functions of SET domain-containing proteins. Trends Biochem. Sci. 38, 621–639 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang, X., Zhou, L. & Cheng, X. Crystal structure of the conserved core of protein arginine methyltransferase PRMT3. EMBO J. 19, 3509–3519 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Weiss, V. H. et al. The structure and oligomerization of the yeast arginine methyltransferase, Hmt1. Nat. Struct. Biol. 7, 1165–1171 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Greer, E. L. & Shi, Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat. Rev. Genet. 13, 343–357 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Lee, J. S., Smith, E. & Shilatifard, A. The language of histone crosstalk. Cell 142, 682–685 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116–120 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Bannister, A. J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001).

    Article  CAS  PubMed  Google Scholar 

  46. Nielsen, P. R. et al. Structure of the HP1 chromodomain bound to histone H3 methylated at lysine 9. Nature 416, 103–107 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Jacobs, S. A. & Khorasanizadeh, S. Structure of HP1 chromodomain bound to a lysine 9-methylated histone H3 tail. Science 295, 2080–2083 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. 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  PubMed  PubMed Central  Google Scholar 

  49. 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  PubMed  PubMed Central  Google Scholar 

  50. Patel, D. J. & Wang, Z. Readout of epigenetic modifications. Annu. Rev. Biochem. 82, 81–118 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Vermeulen, M. et al. Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell 131, 58–69 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Nielsen, S. J. et al. Rb targets histone H3 methylation and HP1 to promoters. Nature 412, 561–565 (2001).

    Article  CAS  PubMed  Google Scholar 

  53. Bannister, A. J., Schneider, R. & Kouzarides, T. Histone methylation: dynamic or static? Cell 109, 801–806 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  55. Allis, C. D., Bowen, J. K., Abraham, G. N., Glover, C. V. & Gorovsky, M. A. Proteolytic processing of histone H3 in chromatin: a physiologically regulated event in Tetrahymena micronuclei. Cell 20, 55–64 (1980).

    Article  CAS  PubMed  Google Scholar 

  56. Humphrey, G. W. et al. Stable histone deacetylase complexes distinguished by the presence of SANT domain proteins CoREST/kiaa0071 and Mta-L1. J. Biol. Chem. 276, 6817–6824 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Shi, Y. et al. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 422, 735–738 (2003).

    Article  CAS  PubMed  Google Scholar 

  58. Tong, J. K., Hassig, C. A., Schnitzler, G. R., Kingston, R. E. & Schreiber, S. L. Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature 395, 917–921 (1998).

    Article  CAS  PubMed  Google Scholar 

  59. You, A., Tong, J. K., Grozinger, C. M. & Schreiber, S. L. CoREST is an integral component of the CoREST- human histone deacetylase complex. Proc. Natl Acad. Sci. USA 98, 1454–1458 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hakimi, M. A. et al. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc. Natl Acad. Sci. USA 99, 7420–7425 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Tsukada, Y. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Whetstine, J. R. et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125, 467–481 (2006).

    Article  CAS  PubMed  Google Scholar 

  65. Fodor, B. D. et al. Jmjd2b antagonizes H3K9 trimethylation at pericentric heterochromatin in mammalian cells. Genes Dev. 20, 1557–1562 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cloos, P. A. et al. The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3. Nature 442, 307–311 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Kooistra, S. M. & Helin, K. Molecular mechanisms and potential functions of histone demethylases. Nat. Rev. Mol. Cell Biol. 13, 297–311 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Brahms, H., Meheus, L., de Brabandere, V., Fischer, U. & Luhrmann, R. Symmetrical dimethylation of arginine residues in spliceosomal Sm protein B/B' and the Sm-like protein LSm4, and their interaction with the SMN protein. RNA 7, 1531–1542 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Friesen, W. J., Massenet, S., Paushkin, S., Wyce, A. & Dreyfuss, G. SMN, the product of the spinal muscular atrophy gene, binds preferentially to dimethylarginine-containing protein targets. Mol. Cell 7, 1111–1117 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Yu, M. C. et al. Arginine methyltransferase affects interactions and recruitment of mRNA processing and export factors. Genes Dev. 18, 2024–2035 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Li, H. et al. Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. Coactivator-associated arginine methyltransferase. J. Biol. Chem. 277, 44623–44630 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Nishida, K. M. et al. Functional involvement of Tudor and dPRMT5 in the piRNA processing pathway in Drosophila germlines. EMBO J. 28, 3820–3831 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Reuter, M. et al. Loss of the Mili-interacting Tudor domain-containing protein-1 activates transposons and alters the Mili-associated small RNA profile. Nat. Struct. Mol. Biol. 16, 639–646 (2009).

    Article  CAS  PubMed  Google Scholar 

  74. Vagin, V. V. et al. Proteomic analysis of murine Piwi proteins reveals a role for arginine methylation in specifying interaction with Tudor family members. Genes Dev. 23, 1749–1762 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chen, C., Nott, T. J., Jin, J. & Pawson, T. Deciphering arginine methylation: Tudor tells the tale. Nat. Rev. Mol. Cell Biol. 12, 629–642 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Clarke, S. G. Protein methylation at the surface and buried deep: thinking outside the histone box. Trends Biochem. Sci. 38, 243–252 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Pahlich, S., Zakaryan, R. P. & Gehring, H. Protein arginine methylation: cellular functions and methods of analysis. Biochim. Biophys. Acta 1764, 1890–1903 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Chuikov, S. et al. Regulation of p53 activity through lysine methylation. Nature 432, 353–360 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Huang, J. et al. Repression of p53 activity by Smyd2- mediated methylation. Nature 444, 629–632 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Shi, X. et al. Modulation of p53 function by SET8-mediated methylation at lysine 382. Mol. Cell 27, 636–646 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Huang, J. et al. G9a and Glp methylate lysine 373 in the tumor suppressor p53. J. Biol. Chem. 285, 9636–9641 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Jansson, M. et al. Arginine methylation regulates the p53 response. Nat. Cell Biol. 10, 1431–1439 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Metzger, E. et al. LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription. Nature 437, 436–439 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Huszar, G. & Elzinga, M. Epsilon-N-methyl lysine in myosin. Nature 223, 834–835 (1969).

    Article  CAS  PubMed  Google Scholar 

  85. DeLange, R. J., Glazer, A. N. & Smith, E. L. Presence and location of an unusual amino acid, epsilon-N-trimethyllysine, in cytochrome c of wheat germ and Neurospora. J. Biol. Chem. 244, 1385–1388 (1969).

    Article  CAS  PubMed  Google Scholar 

  86. Pollack, B. P. et al. The human homologue of the yeast proteins Skb1 and Hsl7p interacts with Jak kinases and contains protein methyltransferase activity. J. Biol. Chem. 274, 31531–31542 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Ong, S. E., Mittler, G. & Mann, M. Identifying and quantifying in vivo methylation sites by heavy methyl SILAC. Nat. Methods 1, 119–126 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Levy, D. et al. A proteomic approach for the identification of novel lysine methyltransferase substrates. Epigenetics Chromatin 4, 19 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Cao, X. J., Arnaudo, A. M. & Garcia, B. A. Large-scale global identification of protein lysine methylation in vivo. Epigenetics 8, 477–485 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Guo, A. et al. Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Mol. Cell. Proteomics 13, 372–387 (2014).

    Article  CAS  PubMed  Google Scholar 

  91. Liu, H. et al. A method for systematic mapping of protein lysine methylation identifies functions for HP1beta in DNA damage response. Mol. Cell 50, 723–735 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Moore, K. E. et al. A general molecular affinity strategy for global detection and proteomic analysis of lysine methylation. Mol. Cell 50, 444–456 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Islam, K. et al. Bioorthogonal profiling of protein methylation using azido derivative of S-adenosyl-L-methionine. J. Am. Chem. Soc. 134, 5909–5915 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Islam, K. et al. Defining efficient enzyme-cofactor pairs for bioorthogonal profiling of protein methylation. Proc. Natl Acad. Sci. USA 110, 16778–16783 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Binda, O. et al. A chemical method for labeling lysine methyltransferase substrates. Chembiochem 12, 330–334 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Peters, W. et al. Enzymatic site-specific functionalization of protein methyltransferase substrates with alkynes for click labeling. Angew. Chem. Int. Ed. 49, 5170–5173 (2010).

    Article  CAS  Google Scholar 

  97. Biggar, K. K. & Li, S. S. Non-histone protein methylation as a regulator of cellular signalling and function. Nat. Rev. Mol. Cell Biol. 16, 5–17 (2015).

    Article  CAS  PubMed  Google Scholar 

  98. Andreu-Perez, P. et al. Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF. Sci. Signal. 4, ra58 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Mazur, P. K. et al. SMYD3 links lysine methylation of MAP3K2 to Ras-driven cancer. Nature 510, 283–287 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Bikkavilli, R. K. et al. Dishevelled3 is a novel arginine methyl transferase substrate. Sci. Rep. 2, 805 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Kim, E. et al. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 23, 839–852 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Levy, D. et al. Lysine methylation of the NF-kappaB subunit RelA by SETD6 couples activity of the histone methyltransferase GLP at chromatin to tonic repression of NF-kappaB signaling. Nat. Immunol. 12, 29–36 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. Kubicek, S. et al. Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol. Cell 25, 473–481 (2007).

    Article  CAS  PubMed  Google Scholar 

  104. Tachibana, M. et al. Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev. 19, 815–826 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Rathert, P. et al. Protein lysine methyltransferase G9a acts on non-histone targets. Nat. Chem. Biol. 4, 344–346 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kaniskan, H. U., Konze, K. D. & Jin, J. Selective inhibitors of protein methyltransferases. J. Med. Chem. 58, 1596–1629 (2015).

    Article  CAS  PubMed  Google Scholar 

  107. Ferguson, A. D. et al. Structural basis of substrate methylation and inhibition of SMYD2. Structure 19, 1262–1273 (2011).

    Article  CAS  PubMed  Google Scholar 

  108. Saddic, L. A. et al. Methylation of the retinoblastoma tumor suppressor by SMYD2. J. Biol. Chem. 285, 37733–37740 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Castillo-Aguilera, O., Depreux, P., Halby, L., Arimondo, P. B. & Goossens, L. DNA methylation targeting: the DNMT/HMT crosstalk challenge. Biomolecules 7, E3 (2017).

    Article  PubMed  CAS  Google Scholar 

  110. Chan-Penebre, E. et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat. Chem. Biol. 11, 432–437 (2015).

    Article  CAS  PubMed  Google Scholar 

  111. Okada, Y. et al. hDOT1L links histone methylation to leukemogenesis. Cell 121, 167–178 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Daigle, S. R. et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20, 53–65 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Daigle, S. R. et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood 122, 1017–1025 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Morin, R. D. et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat. Genet. 42, 181–185 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kleer, C. G. et al. EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc. Natl Acad. Sci. USA 100, 11606–11611 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Varambally, S. et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002).

    Article  CAS  PubMed  Google Scholar 

  118. Sneeringer, C. J. et al. Coordinated activities of wild-type plus mutant EZH2 drive tumor-associated hypertrimethylation of lysine 27 on histone H3 (H3K27) in human B-cell lymphomas. Proc. Natl Acad. Sci. USA 107, 20980–20985 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Knutson, S. K. et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol. 8, 890–896 (2012).

    Article  CAS  PubMed  Google Scholar 

  120. Knutson, S. K. et al. Selective inhibition of EZH2 by EPZ-6438 leads to potent antitumor activity in EZH2-mutant non-Hodgkin lymphoma. Mol. Cancer Ther. 13, 842–854 (2014).

    Article  CAS  PubMed  Google Scholar 

  121. Liu, F. et al. Exploiting an allosteric binding site of PRMT3 yields potent and selective inhibitors. J. Med. Chem. 56, 2110–2124 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Kaniskan, H. U. et al. A potent, selective and cell-active allosteric inhibitor of protein arginine methyltransferase 3 (PRMT3). Angew. Chem. Int. Ed. 54, 5166–5170 (2015).

    Article  CAS  Google Scholar 

  123. Lee, M. G., Wynder, C., Schmidt, D. M., McCafferty, D. G. & Shiekhattar, R. Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem. Biol. 13, 563–567 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Schmidt, D. M. & McCafferty, D. G. trans-2-phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1. Biochemistry 46, 4408–4416 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Binda, C. et al. Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2. J. Am. Chem. Soc. 132, 6827–6833 (2010).

    Article  CAS  PubMed  Google Scholar 

  126. Yang, M. et al. Structural basis for the inhibition of the LSD1 histone demethylase by the antidepressant trans-2-phenylcyclopropylamine. Biochemistry 46, 8058–8065 (2007).

    Article  CAS  PubMed  Google Scholar 

  127. Schenk, T. et al. Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat. Med. 18, 605–611 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Harris, W. J. et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell 21, 473–487 (2012).

    Article  CAS  PubMed  Google Scholar 

  129. Morera, L., Lubbert, M. & Jung, M. Targeting histone methyltransferases and demethylases in clinical trials for cancer therapy. Clin. Epigenetics 8, 57 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Kruidenier, L. et al. A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 488, 404–408 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Hancock, R. L., Dunne, K., Walport, L. J., Flashman, E. & Kawamura, A. Epigenetic regulation by histone demethylases in hypoxia. Epigenomics 7, 791–811 (2015).

    Article  CAS  PubMed  Google Scholar 

  132. Teperino, R., Schoonjans, K. & Auwerx, J. Histone methyl transferases and demethylases; can they link metabolism and transcription? Cell Metab. 12, 321–327 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Shyh-Chang, N. et al. Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science 339, 222–226 (2013).

    Article  PubMed  CAS  Google Scholar 

  134. Ulanovskaya, O. A., Zuhl, A. M. & Cravatt, B. F. NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. Nat. Chem. Biol. 9, 300–306 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Mentch, S. J. et al. Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism. Cell Metab. 22, 861–873 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Carey, B. W., Finley, L. W., Cross, J. R., Allis, C. D. & Thompson, C. B. Intracellular alpha-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518, 413–416 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Ward, P. S. et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17, 225–234 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Hino, S. et al. FAD-dependent lysine-specific demethylase-1 regulates cellular energy expenditure. Nat. Commun. 3, 758 (2012).

    Article  PubMed  CAS  Google Scholar 

  141. Luka, Z., Mudd, S. H. & Wagner, C. Glycine N-methyltransferase and regulation of S-adenosylmethionine levels. J. Biol. Chem. 284, 22507–22511 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Xiao, M. et al. Inhibition of alpha-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326–1338 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Olsen, J. B. et al. Quantitative profiling of the activity of protein lysine methyltransferase SMYD2 using SILAC-based proteomics. Mol. Cell. Proteomics 15, 892–905 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Zee, B. M. & Garcia, B. A. Discovery of lysine post-translational modifications through mass spectrometric detection. Essays Biochem. 52, 147–163 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Ostareck-Lederer, A. et al. Asymmetric arginine dimethylation of heterogeneous nuclear ribonucleoprotein K by protein-arginine methyltransferase 1 inhibits its interaction with c-Src. J. Biol. Chem. 281, 11115–11125 (2006).

    Article  CAS  PubMed  Google Scholar 

  146. Vermeulen, M. et al. Quantitative interaction proteomics and genome-wide profiling of epigenetic histone marks and their readers. Cell 142, 967–980 (2010).

    Article  CAS  PubMed  Google Scholar 

  147. Hu, S. B. et al. Protein arginine methyltransferase CARM1 attenuates the paraspeckle-mediated nuclear retention of mRNAs containing IRAlus. Genes Dev. 29, 630–645 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Castello, A. et al. Comprehensive identification of RNA-binding domains in human cells. Mol. Cell 63, 696–710 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Beaver, J. E. & Waters, M. L. Molecular recognition of Lys and Arg methylation. ACS Chem. Biol. 11, 643–653 (2016).

    Article  CAS  PubMed  Google Scholar 

  150. Barth, T. K. & Imhof, A. Fast signals and slow marks: the dynamics of histone modifications. Trends Biochem. Sci. 35, 618–626 (2010).

    Article  CAS  PubMed  Google Scholar 

  151. Zee, B. M., Levin, R. S., Dimaggio, P. A. & Garcia, B. A. Global turnover of histone post-translational modifications and variants in human cells. Epigenetics Chromatin 3, 22 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Jacobs, S. A. et al. The active site of the SET domain is constructed on a knot. Nat. Struct. Biol. 9, 833–838 (2002).

    CAS  PubMed  Google Scholar 

  153. Min, J., Zhang, X., Cheng, X., Grewal, S. I. & Xu, R. M. Structure of the SET domain histone lysine methyltransferase Clr4. Nat. Struct. Biol. 9, 828–832 (2002).

    CAS  PubMed  Google Scholar 

  154. Trievel, R. C., Beach, B. M., Dirk, L. M., Houtz, R. L. & Hurley, J. H. Structure and catalytic mechanism of a SET domain protein methyltransferase. Cell 111, 91–103 (2002).

    Article  CAS  PubMed  Google Scholar 

  155. Wilson, J. R. et al. Crystal structure and functional analysis of the histone methyltransferase SET7/9. Cell 111, 105–115 (2002).

    Article  CAS  PubMed  Google Scholar 

  156. Zhang, X. et al. Structure of the Neurospora SET domain protein DIM-5, a histone H3 lysine methyltransferase. Cell 111, 117–127 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Lu, X. et al. The effect of H3K79 dimethylation and H4K20 trimethylation on nucleosome and chromatin structure. Nat. Struct. Mol. Biol. 15, 1122–1124 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Pasini, D. et al. Characterization of an antagonistic switch between histone H3 lysine 27 methylation and acetylation in the transcriptional regulation of Polycomb group target genes. Nucleic Acids Res. 38, 4958–4969 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Tie, F. et al. CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing. Development 136, 3131–3141 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank L. Sawyer for help with retrieving information and materials relating to Richard Ambler's research; P. Hornbeck for help with the analyses of known methylated proteins; O. Gozani, J. Olsen and B. Fischer for discussions; and M. Teplova for help with the figures. Work in the laboratory of Y.S. is supported by the US National Institutes of Health (CA118487, GM117264 and MH096066) and Boston Children's Hospital. Y.S. is an American Cancer Society Research Professor. The authors apologize to colleagues whose work could not be cited owing to space limitations.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Jernej Murn or Yang Shi.

Ethics declarations

Competing interests

Y.S. is a co-founder of Constellation Pharmaceuticals, Inc., Cambridge, Massachusetts, USA, and is a member of its scientific advisory board. Y.S. is also a consultant for Active Motif, Carlsbad, California, USA.

Related links

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Murn, J., Shi, Y. The winding path of protein methylation research: milestones and new frontiers. Nat Rev Mol Cell Biol 18, 517–527 (2017). https://doi.org/10.1038/nrm.2017.35

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm.2017.35

This article is cited by

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