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  • Review Article
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The DNA methyltransferase family: a versatile toolkit for epigenetic regulation

Nature Reviews Genetics volume 19, pages 81–92 (2018)Cite this article

Subjects

Key Points

  • The DNA methyltransferases (DNMTs) are a conserved family of cytosine methylases with a key role in epigenetic regulation.

  • DNMT activity is highly regulated. Key regulatory mechanisms include molecular interactions, post-translational modifications, alternative splicing and gene duplication or gene loss.

  • The molecular functions of DNMTs are not limited to gene silencing and can also include transcriptional activation and post-transcriptional regulation. The latter function is mediated by DNMT2-dependent RNA methylation.

  • DNMTs are important for normal mammalian development, and DNMT mutations are associated with several human diseases, including cancer.

Abstract

The DNA methyltransferase (DNMT) family comprises a conserved set of DNA-modifying enzymes that have a central role in epigenetic gene regulation. Recent studies have shown that the functions of the canonical DNMT enzymes — DNMT1, DNMT3A and DNMT3B — go beyond their traditional roles of establishing and maintaining DNA methylation patterns. This Review analyses how molecular interactions and changes in gene copy numbers modulate the activity of DNMTs in diverse gene regulatory functions, including transcriptional silencing, transcriptional activation and post-transcriptional regulation by DNMT2-dependent tRNA methylation. This mechanistic diversity enables the DNMT family to function as a versatile toolkit for epigenetic regulation.

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Figure 1: Conserved domain structures and catalytic mechanism of animal DNA methyltransferase family members.
Figure 2: Evolutionary gains and losses of DNA methyltransferase family genes in animal genomes.
Figure 3: Mechanistic model for a role of DNA methyltransferase family members in retrotransposon silencing.
Figure 4: Mechanistic models for a role of DNA methyltransferase family members in transcriptional activation.
Figure 5: Mechanistic model for a role of DNA methyltransferase 2 in post-transcriptional gene regulation.

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References

  1. Sanchez-Romero, M. A., Cota, I. & Casadesus, J. DNA methylation in bacteria: from the methyl group to the methylome. Curr. Opin. Microbiol. 25, 9–16 (2015).

    Article  CAS  PubMed  Google Scholar 

  2. Feng, S. et al. Conservation and divergence of methylation patterning in plants and animals. Proc. Natl Acad. Sci. USA 107, 8689–8694 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zemach, A., McDaniel, I. E., Silva, P. & Zilberman, D. Genome-wide evolutionary analysis of eukaryotic DNA methylation. Science 328, 916–919 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Holliday, R. & Pugh, J. E. DNA modification mechanisms and gene activity during development. Science 187, 226–232 (1975).

    Article  CAS  PubMed  Google Scholar 

  5. Riggs, A. D. X inactivation, differentiation, and DNA methylation. Cytogenet. Cell Genet. 14, 9–25 (1975).

    Article  CAS  PubMed  Google Scholar 

  6. Koziol, M. J. et al. Identification of methylated deoxyadenosines in vertebrates reveals diversity in DNA modifications. Nat. Struct. Mol. Biol. 23, 24–30 (2016).

    Article  CAS  PubMed  Google Scholar 

  7. Liu, J. et al. Abundant DNA 6mA methylation during early embryogenesis of zebrafish and pig. Nat. Commun. 7, 13052 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wu, J. C. & Santi, D. V. On the mechanism and inhibition of DNA cytosine methyltransferases. Prog. Clin. Biol. Res. 198, 119–129 (1985).

    CAS  PubMed  Google Scholar 

  9. Wu, J. C. & Santi, D. V. Kinetic and catalytic mechanism of HhaI methyltransferase. J. Biol. Chem. 262, 4778–4786 (1987).

    CAS  PubMed  Google Scholar 

  10. Timinskas, A., Butkus, V. & Janulaitis, A. Sequence motifs characteristic for DNA [cytosine-N4] and DNA [adenine-N6] methyltransferases. Classification of all DNA methyltransferases. Gene 157, 3–11 (1995).

    Article  CAS  PubMed  Google Scholar 

  11. Posfai, J., Bhagwat, A. S., Posfai, G. & Roberts, R. J. Predictive motifs derived from cytosine methyltransferases. Nucleic Acids Res. 17, 2421–2435 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bestor, T., Laudano, A., Mattaliano, R. & Ingram, V. Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. J. Mol. Biol. 203, 971–983 (1988).

    Article  CAS  PubMed  Google Scholar 

  13. Ponger, L. & Li, W. H. Evolutionary diversification of DNA methyltransferases in eukaryotic genomes. Mol. Biol. Evol. 22, 1119–1128 (2005).

    Article  CAS  PubMed  Google Scholar 

  14. Law, J. A. & Jacobsen, S. E. Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat. Rev. Genet. 11, 204–220 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cao, X. & Jacobsen, S. E. Role of the arabidopsis DRM methyltransferases in de novo DNA methylation and gene silencing. Curr. Biol. 12, 1138–1144 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Henikoff, S. & Comai, L. A. DNA methyltransferase homolog with a chromodomain exists in multiple polymorphic forms in Arabidopsis. Genetics 149, 307–318 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Huff, J. T. & Zilberman, D. Dnmt1-independent CG methylation contributes to nucleosome positioning in diverse eukaryotes. Cell 156, 1286–1297 (2014). This study provides a key example of how DNMTs can mediate additional epigenetic functions. The results show that DNMT5-mediated CpG methylation regulates nucleosome positioning in marine algae.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Deaton, A. M. & Bird, A. CpG islands and the regulation of transcription. Genes Dev. 25, 1010–1022 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bergman, Y. & Cedar, H. DNA methylation dynamics in health and disease. Nat. Struct. Mol. Biol. 20, 274–281 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Smith, Z. D. & Meissner, A. DNA methylation: roles in mammalian development. Nat. Rev. Genet. 14, 204–220 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Schubeler, D. Function and information content of DNA methylation. Nature 517, 321–326 (2015).

    Article  CAS  PubMed  Google Scholar 

  22. Iurlaro, M., von Meyenn, F. & Reik, W. DNA methylation homeostasis in human and mouse development. Curr. Opin. Genet. Dev. 43, 101–109 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Rountree, M. R., Bachman, K. E. & Baylin, S. B. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat. Genet. 25, 269–277 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Leonhardt, H., Page, A. W., Weier, H. U. & Bestor, T. H. A targeting sequence directs DNA methyltransferase to sites of DNA replication in mammalian nuclei. Cell 71, 865–873 (1992).

    Article  CAS  PubMed  Google Scholar 

  25. Song, J., Rechkoblit, O., Bestor, T. H. & Patel, D. J. Structure of DNMT1-DNA complex reveals a role for autoinhibition in maintenance DNA methylation. Science 331, 1036–1040 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. 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 

  27. Klimasauskas, S., Kumar, S., Roberts, R. J. & Cheng, X. HhaI methyltransferase flips its target base out of the DNA helix. Cell 76, 357–369 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Du, Q., Wang, Z. & Schramm, V. L. Human DNMT1 transition state structure. Proc. Natl Acad. Sci. USA 113, 2916–2921 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jeltsch, A. & Jurkowska, R. Z. Allosteric control of mammalian DNA methyltransferases — a new regulatory paradigm. Nucleic Acids Res. 44, 8556–8575 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Guo, X. et al. Structural insight into autoinhibition and histone H3-induced activation of DNMT3A. Nature 517, 640–644 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Aapola, U. et al. Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, related to the cytosine-5-methyltransferase 3 gene family. Genomics 65, 293–298 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Bourc'his, D., Xu, G. L., Lin, C. S., Bollman, B. & Bestor, T. H. Dnmt3L and the establishment of maternal genomic imprints. Science 294, 2536–2539 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Jia, D., Jurkowska, R. Z., Zhang, X., Jeltsch, A. & Cheng, X. Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 449, 248–251 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bostick, M. et al. UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317, 1760–1764 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Sharif, J. et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450, 908–912 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Hashimoto, H. et al. The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature 455, 826–829 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dennis, K., Fan, T., Geiman, T., Yan, Q. & Muegge, K. Lsh, a member of the SNF2 family, is required for genome-wide methylation. Genes Dev. 15, 2940–2944 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gibbons, R. J. et al. Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation. Nat. Genet. 24, 368–371 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Ren, J. et al. The ATP binding site of the chromatin remodeling homolog Lsh is required for nucleosome density and de novo DNA methylation at repeat sequences. Nucleic Acids Res. 43, 1444–1455 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Termanis, A. et al. The SNF2 family ATPase LSH promotes cell-autonomous de novo DNA methylation in somatic cells. Nucleic Acids Res. 44, 7592–7604 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Di Ruscio, A. et al. DNMT1-interacting RNAs block gene-specific DNA methylation. Nature 503, 371–376 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Holz-Schietinger, C. & Reich, N. O. RNA modulation of the human DNA methyltransferase 3A. Nucleic Acids Res. 40, 8550–8557 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang, G. et al. Small RNA-mediated DNA (cytosine-5) methyltransferase 1 inhibition leads to aberrant DNA methylation. Nucleic Acids Res. 43, 6112–6124 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang, J. et al. The lysine demethylase LSD1 (KDM1) is required for maintenance of global DNA methylation. Nat. Genet. 41, 125–129 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Esteve, P. O. et al. Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells. Proc. Natl Acad. Sci. USA 106, 5076–5081 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Esteve, P. O. et al. A methylation and phosphorylation switch between an adjacent lysine and serine determines human DNMT1 stability. Nat. Struct. Mol. Biol. 18, 42–48 (2011).

    Article  CAS  PubMed  Google Scholar 

  47. Deplus, R. et al. Regulation of DNA methylation patterns by CK2-mediated phosphorylation of Dnmt3a. Cell Rep. 8, 743–753 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Dev, R. R. et al. Cytosine methylation by DNMT2 facilitates stability and survival of HIV-1 RNA in the host cell during infection. Biochem. J. 474, 2009–2026 (2017).

    Article  CAS  PubMed  Google Scholar 

  49. Robertson, K. D. et al. The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors. Nucleic Acids Res. 27, 2291–2298 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ostler, K. R. et al. Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins. Oncogene 26, 5553–5563 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Duymich, C. E., Charlet, J., Yang, X., Jones, P. A. & Liang, G. DNMT3B isoforms without catalytic activity stimulate gene body methylation as accessory proteins in somatic cells. Nat. Commun. 7, 11453 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Bewick, A. J., Vogel, K. J., Moore, A. J. & Schmitz, R. J. Evolution of DNA methylation across insects. Mol. Biol. Evol. 34, 654–665 (2017).

    CAS  PubMed  Google Scholar 

  53. Falckenhayn, C. et al. Characterization of genome methylation patterns in the desert locust Schistocerca gregaria. J. Exp. Biol. 216, 1423–1429 (2013).

    Article  CAS  PubMed  Google Scholar 

  54. Bonasio, R. et al. Genome-wide and caste-specific DNA methylomes of the ants Camponotus floridanus and Harpegnathos saltator. Curr. Biol. 22, 1755–1764 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lyko, F. et al. The honey bee epigenomes: differential methylation of brain DNA in queens and workers. PLoS Biol. 8, e1000506 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Raddatz, G. et al. Dnmt2-dependent methylomes lack defined DNA methylation patterns. Proc. Natl Acad. Sci. USA 110, 8627–8631 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Catania, S. et al. Epigenetic maintenance of DNA methylation after evolutionary loss of the de novo methyltransferase. Preprint at http://www.biorxiv.org/content/early/2017/06/13/149385 (2017).

  58. Kucharski, R., Maleszka, J., Foret, S. & Maleszka, R. Nutritional control of reproductive status in honeybees via DNA methylation. Science 319, 1827–1830 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Alvarado, S., Rajakumar, R., Abouheif, E. & Szyf, M. Epigenetic variation in the Egfr gene generates quantitative variation in a complex trait in ants. Nat. Commun. 6, 6513 (2015).

    Article  CAS  PubMed  Google Scholar 

  60. Barau, J. et al. The DNA methyltransferase DNMT3C protects male germ cells from transposon activity. Science 354, 909–912 (2016). This study identifies DNMT3C as a novel rodent-specific DNMT and provides a key example of how a DNMT gene duplication can provide additional epigenetic regulatory capacity.

    Article  CAS  PubMed  Google Scholar 

  61. Reik, W. Stability and flexibility of epigenetic gene regulation in mammalian development. Nature 447, 425–432 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Sasaki, H. & Matsui, Y. Epigenetic events in mammalian germ-cell development: reprogramming and beyond. Nat. Rev. Genet. 9, 129–140 (2008).

    Article  CAS  PubMed  Google Scholar 

  63. Okano, M., Xie, S. & Li, E. Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases. Nat. Genet. 19, 219–220 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Okano, M., Bell, D. W., Haber, D. A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Ooi, S. K. et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448, 714–717 (2007). This is a landmark study for understanding the targeting of de novo methylation. The results show that DNMT3L selectively binds to H3K4, thus converting transient histone modification marks into stable DNA methylation patterns.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Boulard, M., Edwards, J. R. & Bestor, T. H. FBXL10 protects Polycomb-bound genes from hypermethylation. Nat. Genet. 47, 479–485 (2015).

    Article  CAS  PubMed  Google Scholar 

  67. He, J. et al. Kdm2b maintains murine embryonic stem cell status by recruiting PRC1 complex to CpG islands of developmental genes. Nat. Cell Biol. 15, 373–384 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ramsahoye, B. H. et al. Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc. Natl Acad. Sci. USA 97, 5237–5242 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lister, R. et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462, 315–322 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lister, R. et al. Global epigenomic reconfiguration during mammalian brain development. Science 341, 1237905 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Keown, C. L. et al. Allele-specific non-CG DNA methylation marks domains of active chromatin in female mouse brain. Proc. Natl Acad. Sci. USA 114, E2882–E2890 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Chen, L. et al. MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome. Proc. Natl Acad. Sci. USA 112, 5509–5514 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gabel, H. W. et al. Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature 522, 89–93 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Gruenbaum, Y., Cedar, H. & Razin, A. Substrate and sequence specificity of a eukaryotic DNA methylase. Nature 295, 620–622 (1982).

    Article  CAS  PubMed  Google Scholar 

  75. Bestor, T. H. & Ingram, V. M. Two DNA methyltransferases from murine erythroleukemia cells: purification, sequence specificity, and mode of interaction with DNA. Proc. Natl Acad. Sci. USA 80, 5559–5563 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Jones, P. A. & Liang, G. Rethinking how DNA methylation patterns are maintained. Nat. Rev. Genet. 10, 805–811 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Tiedemann, R. L. et al. Acute depletion redefines the division of labor among DNA methyltransferases in methylating the human genome. Cell Rep. 9, 1554–1566 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Chen, T., Ueda, Y., Dodge, J. E., Wang, Z. & Li, E. Establishment and maintenance of genomic methylation patterns in mouse embryonic stem cells by Dnmt3a and Dnmt3b. Mol. Cell. Biol. 23, 5594–5605 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Arand, J. et al. In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases. PLoS Genet. 8, e1002750 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Raddatz, G., Gao, Q., Bender, S., Jaenisch, R. & Lyko, F. Dnmt3a protects active chromosome domains against cancer-associated hypomethylation. PLoS Genet. 8, e1003146 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Liao, J. et al. Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells. Nat. Genet. 47, 469–478 (2015). This paper provides a systematic and comprehensive characterization of DNMT1-deficient, DNMT3A-deficient and DNMT3B-deficient human ES cells and elucidates the role of these enzymes in DNA methylation and in influencing cellular phenotypes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Klose, R. J. & Bird, A. P. Genomic DNA methylation: the mark and its mediators. Trends Biochem. Sci. 31, 89–97 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Vojta, A. et al. Repurposing the CRISPR-Cas9 system for targeted DNA methylation. Nucleic Acids Res. 44, 5615–5628 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Amabile, A. et al. Inheritable silencing of endogenous genes by hit-and-run targeted epigenetic editing. Cell 167, 219–232.e14 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Liu, X. S. et al. Editing DNA methylation in the mammalian genome. Cell 167, 233–247.e17 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Stepper, P. et al. Efficient targeted DNA methylation with chimeric dCas9-Dnmt3a-Dnmt3L methyltransferase. Nucleic Acids Res. 45, 1703–1713 (2017).

    Article  CAS  PubMed  Google Scholar 

  87. Walsh, C. P., Chaillet, J. R. & Bestor, T. H. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat. Genet. 20, 116–117 (1998).

    Article  CAS  PubMed  Google Scholar 

  88. Miura, A. et al. Mobilization of transposons by a mutation abolishing full DNA methylation in Arabidopsis. Nature 411, 212–214 (2001).

    Article  CAS  PubMed  Google Scholar 

  89. Bourc'his, D. & Bestor, T. H. Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431, 96–99 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Aravin, A. A. et al. A piRNA pathway primed by individual transposons is linked to de novo DNA methylation in mice. Mol. Cell 31, 785–799 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Molaro, A. et al. Two waves of de novo methylation during mouse germ cell development. Genes Dev. 28, 1544–1549 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Manakov, S. A. et al. MIWI2 and MILI have differential effects on piRNA biogenesis and DNA methylation. Cell Rep. 12, 1234–1243 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Challen, G. A. et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44, 23–31 (2012).

    Article  CAS  Google Scholar 

  94. Jeong, M. et al. Large conserved domains of low DNA methylation maintained by Dnmt3a. Nat. Genet. 46, 17–23 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Zhang, X. et al. DNMT3A and TET2 compete and cooperate to repress lineage-specific transcription factors in hematopoietic stem cells. Nat. Genet. 48, 1014–1023 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Domcke, S. et al. Competition between DNA methylation and transcription factors determines binding of NRF1. Nature 528, 575–579 (2015).

    Article  CAS  PubMed  Google Scholar 

  97. Yin, Y. et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors. Science 356, eaaj2239 (2017). This is a comprehensive and systematic study identifying large groups of transcription factors that are positively or negatively affected by DNA methylation. The findings provide a mechanistic explanation for a role of DNA methylation in transcriptional activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Rinaldi, L. et al. Dnmt3a and Dnmt3b associate with enhancers to regulate human epidermal stem cell homeostasis. Cell Stem Cell 19, 491–501 (2016). This study provides a key example of how DNMTs are required for gene activation. The results show that DNMT3A-mediated DNA methylation is required as a substrate for hydroxymethylation-dependent enhancer activation.

    Article  CAS  PubMed  Google Scholar 

  99. Spruijt, C. G. et al. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 152, 1146–1159 (2013).

    Article  CAS  PubMed  Google Scholar 

  100. Iurlaro, M. et al. A screen for hydroxymethylcytosine and formylcytosine binding proteins suggests functions in transcription and chromatin regulation. Genome Biol. 14, R119 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Maunakea, A. K. et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature 466, 253–257 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Baubec, T. et al. Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 520, 243–247 (2015). This is a landmark study that localizes DNMT3B to the bodies of transcribed genes and shows that enzyme targeting is regulated by the SETD2-mediated methylation of H3K36.

    Article  CAS  PubMed  Google Scholar 

  103. Morselli, M. et al. In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse. eLife 4, e06205 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Neri, F. et al. Intragenic DNA methylation prevents spurious transcription initiation. Nature 543, 72–77 (2017).

    Article  CAS  PubMed  Google Scholar 

  105. Wilkinson, C. R., Bartlett, R., Nurse, P. & Bird, A. P. The fission yeast gene pmt1+ encodes a DNA methyltransferase homologue. Nucleic Acids Res. 23, 203–210 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Okano, M., Xie, S. & Li, E. Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells. Nucleic Acids Res. 26, 2536–2540 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Yoder, J. A. & Bestor, T. H. A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast. Hum. Mol. Genet. 7, 279–284 (1998).

    Article  CAS  PubMed  Google Scholar 

  108. Goll, M. G. et al. Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science 311, 395–398 (2006). This is a transformative study that uncovers the tRNA methyltransferase activity of DNMT2 and identifies C38 of tRNA(Asp) as the canonical substrate.

    Article  CAS  PubMed  Google Scholar 

  109. Schaefer, M. et al. RNA methylation by Dnmt2 protects transfer RNAs against stress-induced cleavage. Genes Dev. 24, 1590–1595 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Gray, K. A., Yates, B., Seal, R. L., Wright, M. W. & Bruford, E. A. Genenames.org: the HGNC resources in 2015. Nucleic Acids Res. 43, D1079–D1085 (2015).

    Article  CAS  PubMed  Google Scholar 

  111. Legrand, C. et al. Statistically robust methylation calling for whole-transcriptome bisulfite sequencing reveals distinct methylation patterns for mouse RNAs. Genome Res. 27, 1589–1596 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Jurkowski, T. P. & Jeltsch, A. On the evolutionary origin of eukaryotic DNA methyltransferases and Dnmt2. PLoS ONE 6, e28104 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Jurkowski, T. P. et al. Human DNMT2 methylates tRNAAsp molecules using a DNA methyltransferase-like catalytic mechanism. RNA 14, 1663–1670 (2008). This paper demonstrates that DNMT2 utilizes the catalytic mechanism of DNA methyltransferases for tRNA methylation. This is a key finding illustrating the evolutionary relationship between DNMT2 and the other members of the DNMT family.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Dong, A. et al. Structure of human DNMT2, an enigmatic DNA methyltransferase homolog that displays denaturant-resistant binding to DNA. Nucleic Acids Res. 29, 439–448 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Kaiser, S. et al. The RNA methyltransferase Dnmt2 methylates DNA in the structural context of a tRNA. RNA Biol. http://dx.doi.org/10.1080/15476286.2016.1236170 (2016).

  116. Goll, M. G. & Bestor, T. H. Eukaryotic cytosine methyltransferases. Annu. Rev. Biochem. 74, 481–514 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Durdevic, Z., Mobin, M. B., Hanna, K., Lyko, F. & Schaefer, M. The RNA methyltransferase Dnmt2 is required for efficient dicer-2-dependent siRNA pathway activity in Drosophilia. Cell Rep. 4, 931–937 (2013).

    Article  CAS  PubMed  Google Scholar 

  118. Kiani, J. et al. RNA-mediated epigenetic heredity requires the cytosine methyltransferase Dnmt2. PLoS Genet. 9, e1003498 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Tuorto, F. et al. RNA cytosine methylation by Dnmt2 and NSun2 promotes tRNA stability and protein synthesis. Nat. Struct. Mol. Biol. 19, 900–905 (2012).

    Article  CAS  PubMed  Google Scholar 

  120. Shanmugam, R. et al. Cytosine methylation of tRNA-Asp by DNMT2 has a role in translation of proteins containing poly-Asp sequences. Cell Discov. 1, 15010 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Tuorto, F. et al. The tRNA methyltransferase Dnmt2 is required for accurate polypeptide synthesis during haematopoiesis. EMBO J. 34, 2350–2362 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Li, E., Bestor, T. H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).

    Article  CAS  PubMed  Google Scholar 

  123. Tsumura, A. et al. Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Genes Cells 11, 805–814 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Lei, H. et al. De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells. Development 122, 3195–3205 (1996).

    CAS  PubMed  Google Scholar 

  125. Xie, W. et al. Epigenomic analysis of multilineage differentiation of human embryonic stem cells. Cell 153, 1134–1148 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Gifford, C. A. et al. Transcriptional and epigenetic dynamics during specification of human embryonic stem cells. Cell 153, 1149–1163 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Hansen, R. S. et al. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc. Natl Acad. Sci. USA 96, 14412–14417 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Xu, G. L. et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402, 187–191 (1999).

    Article  CAS  PubMed  Google Scholar 

  129. Thijssen, P. E. et al. Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome. Nat. Commun. 6, 7870 (2015).

    Article  CAS  PubMed  Google Scholar 

  130. Wu, H. et al. Converging disease genes in ICF syndrome: ZBTB24 controls expression of CDCA7 in mammals. Hum. Mol. Genet. 25, 4041–4051 (2016).

    Article  CAS  PubMed  Google Scholar 

  131. Zhu, H. et al. Lsh is involved in de novo methylation of DNA. EMBO J. 25, 335–345 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Klein, C. J. et al. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss. Nat. Genet. 43, 595–600 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Baets, J. et al. Defects of mutant DNMT1 are linked to a spectrum of neurological disorders. Brain 138, 845–861 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Tatton-Brown, K. et al. Mutations in the DNA methyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability. Nat. Genet. 46, 385–388 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Ley, T. J. et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424–2433 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Fan, G. et al. DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J. Neurosci. 21, 788–797 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Sun, Z. et al. Aberrant signature methylome by DNMT1 hot spot mutation in hereditary sensory and autonomic neuropathy 1E. Epigenetics 9, 1184–1193 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Kim, S. J. et al. A DNMT3A mutation common in AML exhibits dominant-negative effects in murine ES cells. Blood 122, 4086–4089 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Russler-Germain, D. A. et al. The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers. Cancer Cell 25, 442–454 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Spencer, D. H. et al. CpG island hypermethylation mediated by DNMT3A is a consequence of AML progression. Cell 168, 801–816.e13 (2017). This study characterizes, in detail, the aberrant methylation patterns found in patients with acute myeloid leukaemia with the most common DNMT3A mutations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Wijmenga, C. et al. Genetic variation in ICF syndrome: evidence for genetic heterogeneity. Hum. Mutat. 16, 509–517 (2000).

    Article  CAS  PubMed  Google Scholar 

  142. Ehrlich, M., Jackson, K. & Weemaes, C. Immunodeficiency, centromeric region instability, facial anomalies syndrome (ICF). Orphanet J. Rare Dis. 1, 2 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Baylin, S. B. & Jones, P. A. A decade of exploring the cancer epigenome — biological and translational implications. Nat. Rev. Cancer 11, 726–734 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Heyn, H. & Esteller, M. DNA methylation profiling in the clinic: applications and challenges. Nat. Rev. Genet. 13, 679–692 (2012).

    Article  CAS  PubMed  Google Scholar 

  145. Jones, P. A., Issa, J. P. & Baylin, S. Targeting the cancer epigenome for therapy. Nat. Rev. Genet. 17, 630–641 (2016).

    Article  CAS  PubMed  Google Scholar 

  146. Ahuja, N., Easwaran, H. & Baylin, S. B. Harnessing the potential of epigenetic therapy to target solid tumors. J. Clin. Invest. 124, 56–63 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Chiappinelli, K. B., Zahnow, C. A., Ahuja, N. & Baylin, S. B. Combining epigenetic and immunotherapy to combat cancer. Cancer Res. 76, 1683–1689 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Stresemann, C. & Lyko, F. Modes of action of the DNA methyltransferase inhibitors azacytidine and decitabine. Int. J. Cancer 123, 8–13 (2008).

    Article  CAS  PubMed  Google Scholar 

  149. Maslov, A. Y. et al. 5-Aza-2′-deoxycytidine-induced genome rearrangements are mediated by DNMT1. Oncogene 31, 5172–5179 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Sorm, F., Piskala, A., Cihak, A. & Vesely, J. 5-Azacytidine, a new, highly effective cancerostatic. Experientia 20, 202–203 (1964).

    Article  CAS  PubMed  Google Scholar 

  151. Jones, P. A. & Taylor, S. M. Cellular differentiation, cytidine analogs and DNA methylation. Cell 20, 85–93 (1980).

    Article  CAS  PubMed  Google Scholar 

  152. Laird, P. W. et al. Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81, 197–205 (1995).

    Article  CAS  PubMed  Google Scholar 

  153. Linhart, H. G. et al. Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genes Dev. 21, 3110–3122 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Rasmussen, K. D. & Helin, K. Role of TET enzymes in DNA methylation, development, and cancer. Genes Dev. 30, 733–750 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Hon, G. C. et al. 5mC Oxidation by Tet2 modulates enhancer activity and timing of transcriptome reprogramming during differentiation. Mol. Cell 56, 286–297 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Lu, F., Liu, Y., Jiang, L., Yamaguchi, S. & Zhang, Y. Role of Tet proteins in enhancer activity and telomere elongation. Genes Dev. 28, 2103–2119 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Jeltsch, A., Nellen, W. & Lyko, F. Two substrates are better than one: dual specificities for Dnmt2 methyltransferases. Trends Biochem. Sci. 31, 306–308 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The author would like to thank the members of his group for constructive comments on the manuscript. Work in the Lyko laboratory is supported by grants from the Deutsche Forschungsgemeinschaft, Landesstiftung Baden-Württemberg and the Helmholtz-Israel-Cooperation in Personalized Medicine.

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  1. Division of Epigenetics, DKFZ–ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 580, Heidelberg, 69120, Germany

    Frank Lyko

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PowerPoint slides

Glossary

CpG methylation

Methylation of a cytosine that is next to a guanine. CpG dinucleotides are strand-symmetric and thus allow the postreplicative copying of methylation patterns from the parental strand to the newly synthesized strand.

Chromodomain

A conserved protein domain of 40–50 amino acid residues that mediates chromatin interactions.

DNMT1-associated protein 1 (DMAP1) binding domain

A binding domain for DMAP1, a protein that links DNA methyltransferase 1 (DNMT1) to histone acetylation.

Replication foci targeting sequence

(RFTS). A DNA methyltransferase 1 (DNMT1)-specific domain that targets the enzyme to replication foci and thus promotes postreplicative maintenance methylation.

CXXC domain

A zinc-finger domain that contains eight conserved cysteine residues and mediates binding to unmethylated CpG dinucleotides.

Bromo-adjacent homology (BAH) domains

Conserved domains with unknown function that are found in several chromatin-associated proteins.

Pro-Trp-Trp-Pro (PWWP) domain

A protein–protein interaction domain that mediates the binding of DNA methyltransferase 3A (DNMT3A) and DNMT3B to histone H3 molecules that are trimethylated at lysine 36.

ATRX–DNMT3–DNMT3L (ADD) domain

A zinc-finger domain that is present in proteins associated with DNA methylation. This domain mediates targeting of DNA methyltransferase 3 (DNMT3) complexes to histone H3 molecules that are unmethylated at lysine 4.

Maintenance methylation

The postreplicative copying of methylation patterns in CpG dinucleotides from the parental strand to the newly synthesized (and unmethylated) daughter strand.

SET- and RING-associated (SRA) domain

A protein domain with diverse functions that are related to chromatin interactions.

De novo methylation

Methylation of unmethylated DNA for the establishment of new methylation patterns.

CpG islands

Genomic regions with a locally increased density of CpG dinucleotides. CpG islands are often found around promoter regions, are enriched for transcription factor binding sites and are unmethylated.

SELEX

Systematic evolution of ligands by exponential enrichment. A method that identifies the consensus sequence for nucleic acid binding proteins through repeated cycles of binding selection and PCR amplification.

Cryptic promoters

Promoters that do not have a standard initiation site and are normally inactive. The activation of intragenic cryptic promoters can result in altered mRNAs that produce aberrant proteins.

CFT motif

A Cys-Phe-Thr tripeptide between the catalytic motifs VIII and IX that is specific to DNA methyltransferase 2 (DNMT2) enzymes and not found in any other cytosine-5 DNMTs.

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Lyko, F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet 19, 81–92 (2018). https://doi.org/10.1038/nrg.2017.80

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