Establishment, Erasure and Synthetic Reprogramming of DNA Methylation in Mammalian Cells

Part of the RNA Technologies book series (RNATECHN)


DNA methylation is a crucial epigenetic modification involved in the control of cellular function and the balance between generation of DNA methylation and its removal is important for human health. This chapter focuses on the enzymatic machinery responsible for the processes of establishment, maintenance and removal of DNA methylation patterns in mammals. We describe the biochemical, structural and enzymatic properties of DNA methyltransferases and TET DNA hydroxylases, as well as their regulation in cells. We discuss how these enzymes are recruited to specific genomic loci, and how their chromatin interactions, as well as their intrinsic sequence specificities and molecular mechanisms contribute to the methylation pattern of the cell. Finally, we introduce the concept of epigenetic (re)programming, in which designer epigenetic editing tools consisting of a DNA targeting domain fused to an epigenetic editor domain can be used to edit the epigenetic state of a given locus in the genome in order to dissect the functional role of DNA methylation and demethylation. We discuss the promises of this emerging technology for studying epigenetic processes in cells and for engineering of cellular states.


DNA methylation DNA demethylation Synthetic epigenetics TET DNMT dCas9 Epigenetic editing 



We apologize to the authors whose work could not be cited due to the space limitations. Work in the authors laboratory has been supported by Boehringer Ingelheim (R.Z.J) and DFG SPP1784 (T.P.J).


  1. Amabile A, Migliara A, Capasso P et al (2016) Inheritable silencing of endogenous genes by hit-and-run targeted epigenetic editing. Cell 167:219–232, e214PubMedPubMedCentralCrossRefGoogle Scholar
  2. Arita K, Ariyoshi M, Tochio H et al (2008) Recognition of hemi-methylated DNA by the SRA protein UHRF1 by a base-flipping mechanism. Nature 455:818–821CrossRefPubMedGoogle Scholar
  3. Barau J, Teissandier A, Zamudio N et al (2016) The DNA methyltransferase DNMT3C protects male germ cells from transposon activity. Science 354:909–912PubMedCrossRefGoogle Scholar
  4. Basanta-Sanchez M, Wang R, Liu Z et al (2017) TET1-mediated oxidation of 5-formylcytosine (5fC) to 5-carboxycytosine (5caC) in RNA. Chembiochem 18:72–76PubMedCrossRefGoogle Scholar
  5. Bashtrykov P, Jankevicius G, Smarandache A et al (2012) Specificity of Dnmt1 for methylation of hemimethylated CpG sites resides in its catalytic domain. Chem Biol 19:572–578PubMedCrossRefGoogle Scholar
  6. Bashtrykov P, Jankevicius G, Jurkowska RZ et al (2014) The UHRF1 protein stimulates the activity and specificity of the maintenance DNA methyltransferase DNMT1 by an allosteric mechanism. J Biol Chem 289:4106–4115PubMedCrossRefGoogle Scholar
  7. Baubec T, Colombo DF, Wirbelauer C et al (2015) Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation. Nature 520:243–247PubMedCrossRefGoogle Scholar
  8. Bergman Y, Cedar H (2013) DNA methylation dynamics in health and disease. Nat Struct Mol Biol 20:274–281PubMedCrossRefGoogle Scholar
  9. Birney E, Smith GD, Greally JM (2016) Epigenome-wide association studies and the interpretation of disease -omics. PLoS Genet 12:e1006105PubMedPubMedCentralCrossRefGoogle Scholar
  10. Boch J, Bonas U (2010) Xanthomonas AvrBs3 family-type III effectors: discovery and function. Annu Rev Phytopathol 48:419–436PubMedCrossRefGoogle Scholar
  11. Boch J, Scholze H, Schornack S et al (2009) Breaking the code of DNA binding specificity of TAL-type III effectors. Science 326:1509–1512PubMedCrossRefGoogle Scholar
  12. Bogdanovic O, Lister R (2017) DNA methylation and the preservation of cell identity. Curr Opin Genet Dev 46:9–14PubMedCrossRefGoogle Scholar
  13. Bostick M, Kim JK, Esteve PO et al (2007) UHRF1 plays a role in maintaining DNA methylation in mammalian cells. Science 317:1760–1764PubMedCrossRefGoogle Scholar
  14. Bruniquel D, Schwartz RH (2003) Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol 4:235–240PubMedCrossRefGoogle Scholar
  15. Chedin F, Lieber MR, Hsieh CL (2002) The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a. Proc Natl Acad Sci U S A 99:16916–16921PubMedPubMedCentralCrossRefGoogle Scholar
  16. Chen Q, Chen Y, Bian C et al (2013) TET2 promotes histone O-GlcNAcylation during gene transcription. Nature 493:561–564PubMedCrossRefGoogle Scholar
  17. Cheng X, Blumenthal RM (2008) Mammalian DNA methyltransferases: a structural perspective. Structure 16:341–350PubMedPubMedCentralCrossRefGoogle Scholar
  18. Costa Y, Ding J, Theunissen TW et al (2013) NANOG-dependent function of TET1 and TET2 in establishment of pluripotency. Nature 495:370–374PubMedPubMedCentralCrossRefGoogle Scholar
  19. Crawford DJ, Liu MY, Nabel CS et al (2016) Tet2 catalyzes stepwise 5-methylcytosine oxidation by an iterative and de novo mechanism. J Am Chem Soc 138:730–733PubMedPubMedCentralCrossRefGoogle Scholar
  20. Delatte B, Wang F, Ngoc LV et al (2016) RNA biochemistry. Transcriptome-wide distribution and function of RNA hydroxymethylcytosine. Science 351:282–285PubMedCrossRefGoogle Scholar
  21. DeNizio JE, Liu MY, Leddin E et al (2018) Selectivity and promiscuity in TET-mediated oxidation of 5-methylcytosine in DNA and RNA. Biochemistry. PubMedCrossRefGoogle Scholar
  22. Dhayalan A, Rajavelu A, Rathert P et al (2010) The Dnmt3a PWWP domain reads histone 3 lysine 36 trimethylation and guides DNA methylation. J Biol Chem 285:26114–26120PubMedPubMedCentralCrossRefGoogle Scholar
  23. Dunwell TL, McGuffin LJ, Dunwell JM et al (2013) The mysterious presence of a 5-methylcytosine oxidase in the Drosophila genome: possible explanations. Cell Cycle 12:3357–3365PubMedPubMedCentralCrossRefGoogle Scholar
  24. Egger G, Liang G, Aparicio A et al (2004) Epigenetics in human disease and prospects for epigenetic therapy. Nature 429:457–463PubMedCrossRefGoogle Scholar
  25. Egger G, Jeong S, Escobar SG et al (2006) Identification of DNMT1 (DNA methyltransferase 1) hypomorphs in somatic knockouts suggests an essential role for DNMT1 in cell survival. Proc Natl Acad Sci U S A 103:14080–14085PubMedPubMedCentralCrossRefGoogle Scholar
  26. Emperle M, Rajavelu A, Reinhardt R et al (2014) Cooperative DNA binding and protein/DNA fiber formation increases the activity of the Dnmt3a DNA methyltransferase. J Biol Chem 289:29602–29613PubMedPubMedCentralCrossRefGoogle Scholar
  27. Ernst J, Kheradpour P, Mikkelsen TS et al (2011) Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473:43–49PubMedPubMedCentralCrossRefGoogle Scholar
  28. Fu L, Guerrero CR, Zhong N et al (2014) Tet-mediated formation of 5-hydroxymethylcytosine in RNA. J Am Chem Soc 136:11582–11585PubMedPubMedCentralCrossRefGoogle Scholar
  29. Galonska C, Charlton J, Mattei AL et al (2018) Genome-wide tracking of dCas9-methyltransferase footprints. Nat Commun 9:597PubMedPubMedCentralCrossRefGoogle Scholar
  30. Gowher H, Jeltsch A (2001) Enzymatic properties of recombinant Dnmt3a DNA methyltransferase from mouse: the enzyme modifies DNA in a non-processive manner and also methylates non-CpG [correction of non-CpA] sites. J Mol Biol 309:1201–1208PubMedCrossRefGoogle Scholar
  31. Gowher H, Jeltsch A (2002) Molecular enzymology of the catalytic domains of the Dnmt3a and Dnmt3b DNA methyltransferases. J Biol Chem 277:20409–20414PubMedCrossRefGoogle Scholar
  32. Gowher H, Jeltsch A (2018) Mammalian DNA methyltransferases: new discoveries and open questions. Biochem Soc Trans 46:1191–1202PubMedCrossRefGoogle Scholar
  33. Gowher H, Liebert K, Hermann A et al (2005) Mechanism of stimulation of catalytic activity of Dnmt3A and Dnmt3B DNA-(cytosine-C5)-methyltransferases by Dnmt3L. J Biol Chem 280:13341–13348PubMedCrossRefGoogle Scholar
  34. Gowher H, Loutchanwoot P, Vorobjeva O et al (2006) Mutational analysis of the catalytic domain of the murine Dnmt3a DNA-(cytosine C5)-methyltransferase. J Mol Biol 357:928–941PubMedCrossRefGoogle Scholar
  35. Goyal R, Reinhardt R, Jeltsch A (2006) Accuracy of DNA methylation pattern preservation by the Dnmt1 methyltransferase. Nucleic Acids Res 34:1182–1188PubMedPubMedCentralCrossRefGoogle Scholar
  36. Guo F, Li X, Liang D et al (2014) Active and passive demethylation of male and female pronuclear DNA in the mammalian zygote. Cell Stem Cell 15:447–459PubMedCrossRefGoogle Scholar
  37. Guo X, Wang L, Li J et al (2015) Structural insight into autoinhibition and histone H3-induced activation of DNMT3A. Nature 517:640–644CrossRefGoogle Scholar
  38. Hajkova P, Erhardt S, Lane N et al (2002) Epigenetic reprogramming in mouse primordial germ cells. Mech Dev 117:15–23PubMedCrossRefGoogle Scholar
  39. Handa V, Jeltsch A (2005) Profound flanking sequence preference of Dnmt3a and Dnmt3b mammalian DNA methyltransferases shape the human epigenome. J Mol Biol 348:1103–1112PubMedCrossRefGoogle Scholar
  40. Harrison JS, Cornett EM, Goldfarb D et al (2016) Hemi-methylated DNA regulates DNA methylation inheritance through allosteric activation of H3 ubiquitylation by UHRF1. elife 5:e17101PubMedPubMedCentralCrossRefGoogle Scholar
  41. Hashimoto H, Horton JR, Zhang X et al (2008) The SRA domain of UHRF1 flips 5-methylcytosine out of the DNA helix. Nature 455:826–829PubMedPubMedCentralCrossRefGoogle Scholar
  42. Hausinger RP, Schofield CJ (2015) 2-oxoglutarate-dependent oxygenases. RSC metallobiology, vol 3. Royal Society of Chemistry, CambridgeGoogle Scholar
  43. He Y, Ecker JR (2015) Non-CG methylation in the human genome. Annu Rev Genomics Hum Genet 16:55–77PubMedPubMedCentralCrossRefGoogle Scholar
  44. He YF, Li BZ, Li Z et al (2011) Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333:1303–1307PubMedPubMedCentralCrossRefGoogle Scholar
  45. Hermann A, Goyal R, Jeltsch A (2004) The Dnmt1 DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites. J Biol Chem 279:48350–48359PubMedCrossRefGoogle Scholar
  46. Hodges E, Smith AD, Kendall J et al (2009) High definition profiling of mammalian DNA methylation by array capture and single molecule bisulfite sequencing. Genome Res 19:1593–1605PubMedPubMedCentralCrossRefGoogle Scholar
  47. Hsu PD, Lander ES, Zhang F (2014) Development and applications of CRISPR-Cas9 for genome engineering. Cell 157:1262–1278PubMedPubMedCentralCrossRefGoogle Scholar
  48. Hu L, Li Z, Cheng J et al (2013) Crystal structure of TET2-DNA complex: insight into TET-mediated 5mC oxidation. Cell 155:1545–1555PubMedCrossRefGoogle Scholar
  49. Hu L, Lu J, Cheng J et al (2015) Structural insight into substrate preference for TET-mediated oxidation. Nature 527:118–122PubMedCrossRefGoogle Scholar
  50. Huang YH, Su J, Lei Y et al (2017) DNA epigenome editing using CRISPR-Cas SunTag-directed DNMT3A. Genome Biol 18:176PubMedPubMedCentralCrossRefGoogle Scholar
  51. Iida T, Suetake I, Tajima S et al (2002) PCNA clamp facilitates action of DNA cytosine methyltransferase 1 on hemimethylated DNA. Genes Cells 7:997–1007PubMedCrossRefGoogle Scholar
  52. Ito S, Shen L, Dai Q et al (2011) Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333:1300–1303PubMedPubMedCentralCrossRefGoogle Scholar
  53. Iyer LM, Tahiliani M, Rao A et al (2009) Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids. Cell Cycle 8:1698–1710PubMedPubMedCentralCrossRefGoogle Scholar
  54. Jang HS, Shin WJ, Lee JE et al (2017) CpG and non-CpG methylation in epigenetic gene regulation and brain function. Genes (Basel) 8(6). pii: E148Google Scholar
  55. Jeltsch A, Jurkowska RZ (2013) Multimerization of the dnmt3a DNA methyltransferase and its functional implications. Prog Mol Biol Transl Sci 117:445–464PubMedCrossRefGoogle Scholar
  56. Jeltsch A, Jurkowska RZ (2014) New concepts in DNA methylation. Trends Biochem Sci 39:310–318PubMedCrossRefGoogle Scholar
  57. Jeltsch A, Jurkowska RZ (2016) Allosteric control of mammalian DNA methyltransferases – a new regulatory paradigm. Nucleic Acids Res 44:8556–8575PubMedPubMedCentralCrossRefGoogle Scholar
  58. Jia D, Jurkowska RZ, Zhang X et al (2007) Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 449:248–251PubMedPubMedCentralCrossRefGoogle Scholar
  59. Jin SG, Zhang ZM, Dunwell TL et al (2016) Tet3 reads 5-carboxylcytosine through its CXXC domain and is a potential guardian against neurodegeneration. Cell Rep 14:493–505PubMedPubMedCentralCrossRefGoogle Scholar
  60. Jinek M, Chylinski K, Fonfara I et al (2012) A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337:816–821PubMedPubMedCentralCrossRefGoogle Scholar
  61. Jurkowska RZ, Jeltsch A (2016) Enzymology of mammalian DNA methyltransferases. Adv Exp Med Biol 945:87–122PubMedCrossRefGoogle Scholar
  62. Jurkowska RZ, Anspach N, Urbanke C et al (2008) Formation of nucleoprotein filaments by mammalian DNA methyltransferase Dnmt3a in complex with regulator Dnmt3L. Nucleic Acids Res 36:6656–6663PubMedPubMedCentralCrossRefGoogle Scholar
  63. Jurkowska RZ, Jurkowski TP, Jeltsch A (2011a) Structure and function of mammalian DNA methyltransferases. Chembiochem 12:206–222PubMedCrossRefGoogle Scholar
  64. Jurkowska RZ, Siddique AN, Jurkowski TP et al (2011b) Approaches to enzyme and substrate design of the murine Dnmt3a DNA methyltransferase. Chembiochem 12:1589–1594PubMedCrossRefGoogle Scholar
  65. Jurkowski TP, Anspach N, Kulishova L et al (2007) The M.EcoRV DNA-(adenine N6)-methyltransferase uses DNA bending for recognition of an expanded EcoDam recognition site. J Biol Chem 282:36942–36952PubMedCrossRefGoogle Scholar
  66. Jurkowski TP, Ravichandran M, Stepper P (2015) Synthetic epigenetics-towards intelligent control of epigenetic states and cell identity. Clin Epigenetics 7:18PubMedPubMedCentralCrossRefGoogle Scholar
  67. Kinde B, Gabel HW, Gilbert CS et al (2015) Reading the unique DNA methylation landscape of the brain: non-CpG methylation, hydroxymethylation, and MeCP2. Proc Natl Acad Sci U S A 112:6800–6806PubMedPubMedCentralCrossRefGoogle Scholar
  68. Klimasauskas S, Kumar S, Roberts RJ et al (1994) HhaI methyltransferase flips its target base out of the DNA helix. Cell 76:357–369PubMedCrossRefGoogle Scholar
  69. Koch A, Joosten SC, Feng Z et al (2018) Analysis of DNA methylation in cancer: location revisited. Nat Rev Clin Oncol 15:459–466PubMedCrossRefGoogle Scholar
  70. Kolasinska-Zwierz P, Down T, Latorre I et al (2009) Differential chromatin marking of introns and expressed exons by H3K36me3. Nat Genet 41:376–381PubMedPubMedCentralCrossRefGoogle Scholar
  71. Kungulovski G, Nunna S, Thomas M et al (2015) Targeted epigenome editing of an endogenous locus with chromatin modifiers is not stably maintained. Epigenetics Chromatin 8:12PubMedPubMedCentralCrossRefGoogle Scholar
  72. Lau CH, Suh Y (2018) In vivo epigenome editing and transcriptional modulation using CRISPR technology. Transgenic Res 27:489–509PubMedCrossRefGoogle Scholar
  73. Lei Y, Zhang X, Su J et al (2017) Targeted DNA methylation in vivo using an engineered dCas9-MQ1 fusion protein. Nat Commun 8:16026PubMedPubMedCentralCrossRefGoogle Scholar
  74. Lei Y, Huang YH, Goodell MA (2018) DNA methylation and de-methylation using hybrid site-targeting proteins. Genome Biol 19:187PubMedPubMedCentralCrossRefGoogle Scholar
  75. Li BZ, Huang Z, Cui QY et al (2011) Histone tails regulate DNA methylation by allosterically activating de novo methyltransferase. Cell Res 21:1172–1181PubMedPubMedCentralCrossRefGoogle Scholar
  76. Lin L, Liu Y, Xu F et al (2018) Genome-wide determination of on-target and off-target characteristics for RNA-guided DNA methylation by dCas9 methyltransferases. GigaScience 7:1–19PubMedGoogle Scholar
  77. Little EJ, Babic AC, Horton NC (2008) Early interrogation and recognition of DNA sequence by indirect readout. Structure 16:1828–1837PubMedPubMedCentralCrossRefGoogle Scholar
  78. Liu XS, Wu H, Ji X et al (2016) Editing DNA methylation in the mammalian genome. Cell 167:233–247 e217PubMedPubMedCentralCrossRefGoogle Scholar
  79. Liu MY, Torabifard H, Crawford DJ et al (2017) Mutations along a TET2 active site scaffold stall oxidation at 5-hydroxymethylcytosine. Nat Chem Biol 13:181–187PubMedCrossRefGoogle Scholar
  80. Liu XS, Wu H, Krzisch M et al (2018) Rescue of fragile X syndrome neurons by DNA methylation editing of the FMR1 gene. Cell 172:979–992 e976PubMedPubMedCentralCrossRefGoogle Scholar
  81. Maiti A, Drohat AC (2011) Thymine DNA glycosylase can rapidly excise 5-formylcytosine and 5-carboxylcytosine: potential implications for active demethylation of CpG sites. J Biol Chem 286:35334–35338PubMedPubMedCentralCrossRefGoogle Scholar
  82. Martinowich K, Hattori D, Wu H et al (2003) DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302:890–893PubMedCrossRefGoogle Scholar
  83. Mayer W, Niveleau A, Walter J et al (2000) Demethylation of the zygotic paternal genome. Nature 403:501–502PubMedCrossRefGoogle Scholar
  84. McDonald JI, Celik H, Rois LE et al (2016) Reprogrammable CRISPR/Cas9-based system for inducing site-specific DNA methylation. Biol Open 5:866–874PubMedPubMedCentralCrossRefGoogle Scholar
  85. Meissner A, Mikkelsen TS, Gu H et al (2008) Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454:766–770PubMedPubMedCentralCrossRefGoogle Scholar
  86. Mojica FJ, Diez-Villasenor C, Garcia-Martinez J et al (2005) Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements. J Mol Evol 60:174–182PubMedCrossRefGoogle Scholar
  87. Morselli M, Pastor WA, Montanini B et al (2015) In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse. elife 4:e06205PubMedPubMedCentralCrossRefGoogle Scholar
  88. Muller U, Bauer C, Siegl M et al (2014) TET-mediated oxidation of methylcytosine causes TDG or NEIL glycosylase dependent gene reactivation. Nucleic Acids Res 42:8592–8604PubMedPubMedCentralCrossRefGoogle Scholar
  89. Nady N, Lemak A, Walker JR et al (2011) Recognition of multivalent histone states associated with heterochromatin by UHRF1 protein. J Biol Chem 286:24300–24311PubMedPubMedCentralCrossRefGoogle Scholar
  90. Neri F, Rapelli S, Krepelova A et al (2017) Intragenic DNA methylation prevents spurious transcription initiation. Nature 543:72–77PubMedCrossRefGoogle Scholar
  91. Nishiyama A, Yamaguchi L, Sharif J et al (2013) Uhrf1-dependent H3K23 ubiquitylation couples maintenance DNA methylation and replication. Nature 502:249–253PubMedCrossRefGoogle Scholar
  92. Noh KM, Wang H, Kim HR et al (2015) Engineering of a histone-recognition domain in Dnmt3a alters the epigenetic landscape and phenotypic features of mouse ESCs. Mol Cell 59:89–103PubMedPubMedCentralCrossRefGoogle Scholar
  93. Norvil AB, Petell CJ, Alabdi L et al (2018) Dnmt3b methylates DNA by a noncooperative mechanism, and its activity is unaffected by manipulations at the predicted dimer interface. Biochemistry 57:4312–4324PubMedCrossRefGoogle Scholar
  94. Nunna S, Reinhardt R, Ragozin S et al (2014) Targeted methylation of the epithelial cell adhesion molecule (EpCAM) promoter to silence its expression in ovarian cancer cells. PLoS One 9:e87703PubMedPubMedCentralCrossRefGoogle Scholar
  95. Oswald J, Engemann S, Lane N et al (2000) Active demethylation of the paternal genome in the mouse zygote. Curr Biol 10:475–478PubMedCrossRefGoogle Scholar
  96. Otani J, Nankumo T, Arita K et al (2009) Structural basis for recognition of H3K4 methylation status by the DNA methyltransferase 3A ATRX-DNMT3-DNMT3L domain. EMBO Rep 10:1235–1241PubMedPubMedCentralCrossRefGoogle Scholar
  97. Pabo CO, Peisach E, Grant RA (2001) Design and selection of novel Cys2His2 zinc finger proteins. Annu Rev Biochem 70:313–340PubMedCrossRefGoogle Scholar
  98. Parrilla-Doblas JT, Ariza RR, Roldan-Arjona T (2017) Targeted DNA demethylation in human cells by fusion of a plant 5-methylcytosine DNA glycosylase to a sequence-specific DNA binding domain. Epigenetics 12:296–303PubMedPubMedCentralCrossRefGoogle Scholar
  99. Perera A, Eisen D, Wagner M et al (2015) TET3 is recruited by REST for context-specific hydroxymethylation and induction of gene expression. Cell Rep 11:283–294PubMedCrossRefGoogle Scholar
  100. Petell CJ, Alabdi L, He M et al (2016) An epigenetic switch regulates de novo DNA methylation at a subset of pluripotency gene enhancers during embryonic stem cell differentiation. Nucleic Acids Res 44:7605–7617PubMedPubMedCentralCrossRefGoogle Scholar
  101. Pfaffeneder T, Spada F, Wagner M et al (2014) Tet oxidizes thymine to 5-hydroxymethyluracil in mouse embryonic stem cell DNA. Nat Chem Biol 10:574–581PubMedCrossRefGoogle Scholar
  102. Qi LS, Larson MH, Gilbert LA et al (2013) Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell 152:1173–1183PubMedPubMedCentralCrossRefGoogle Scholar
  103. Qin W, Wolf P, Liu N et al (2015) DNA methylation requires a DNMT1 ubiquitin interacting motif (UIM) and histone ubiquitination. Cell Res 25:911–929PubMedPubMedCentralCrossRefGoogle Scholar
  104. Qiu C, Sawada K, Zhang X et al (2002) The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds. Nat Struct Biol 9:217–224PubMedPubMedCentralGoogle Scholar
  105. Rajavelu A, Lungu C, Emperle M et al (2018) Chromatin-dependent allosteric regulation of DNMT3A activity by MeCP2. Nucleic Acids Res 46:9044–9056PubMedPubMedCentralCrossRefGoogle Scholar
  106. Ramsahoye BH, Biniszkiewicz D, Lyko F et al (2000) Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci U S A 97:5237–5242PubMedPubMedCentralCrossRefGoogle Scholar
  107. Ravichandran M, Jurkowska RZ, Jurkowski TP (2018) Target specificity of mammalian DNA methylation and demethylation machinery. Org Biomol Chem 16:1419–1435PubMedCrossRefGoogle Scholar
  108. Rondelet G, Dal Maso T, Willems L et al (2016) Structural basis for recognition of histone H3K36me3 nucleosome by human de novo DNA methyltransferases 3A and 3B. J Struct Biol 194:357–367PubMedCrossRefGoogle Scholar
  109. Rothbart SB, Krajewski K, Nady N et al (2012) Association of UHRF1 with methylated H3K9 directs the maintenance of DNA methylation. Nat Struct Mol Biol 19:1155–1160PubMedPubMedCentralCrossRefGoogle Scholar
  110. Saunderson EA, Stepper P, Gomm JJ et al (2017) Hit-and-run epigenetic editing prevents senescence entry in primary breast cells from healthy donors. Nat Commun 8:1450PubMedPubMedCentralCrossRefGoogle Scholar
  111. Scholze H, Boch J (2010) TAL effector-DNA specificity. Virulence 1:428–432PubMedCrossRefGoogle Scholar
  112. Schubeler D (2015) Function and information content of DNA methylation. Nature 517:321–326PubMedCrossRefGoogle Scholar
  113. Serandour AA, Avner S, Mahe EA et al (2016) Single-CpG resolution mapping of 5-hydroxymethylcytosine by chemical labeling and exonuclease digestion identifies evolutionarily unconserved CpGs as TET targets. Genome Biol 17:56PubMedPubMedCentralCrossRefGoogle Scholar
  114. Sharif J, Muto M, Takebayashi S et al (2007) The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450:908–912PubMedCrossRefGoogle Scholar
  115. Siddique AN, Nunna S, Rajavelu A et al (2013) Targeted methylation and gene silencing of VEGF-A in human cells by using a designed Dnmt3a-Dnmt3L single-chain fusion protein with increased DNA methylation activity. J Mol Biol 425:479–491PubMedCrossRefGoogle Scholar
  116. Smith ZD, Meissner A (2013) DNA methylation: roles in mammalian development. Nat Rev Genet 14:204–220PubMedCrossRefGoogle Scholar
  117. Song J, Teplova M, Ishibe-Murakami S et al (2012) Structure-based mechanistic insights into DNMT1-mediated maintenance DNA methylation. Science 335:709–712PubMedPubMedCentralCrossRefGoogle Scholar
  118. Stepper P, Kungulovski G, Jurkowska RZ et al (2017) Efficient targeted DNA methylation with chimeric dCas9-Dnmt3a-Dnmt3L methyltransferase. Nucleic Acids Res 45:1703–1713PubMedCrossRefGoogle Scholar
  119. Stolzenburg S, Rots MG, Beltran AS et al (2012) Targeted silencing of the oncogenic transcription factor SOX2 in breast cancer. Nucleic Acids Res 40:6725–6740PubMedPubMedCentralCrossRefGoogle Scholar
  120. Stroynowska-Czerwinska A, Piasecka A, Bochtler M (2018) Specificity of MLL1 and TET3 CXXC domains towards naturally occurring cytosine modifications. Biochim Biophys Acta Gene Regul Mech 1861:1093–1101PubMedCrossRefGoogle Scholar
  121. Sutcliffe JS, Nelson DL, Zhang F et al (1992) DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum Mol Genet 1:397–400PubMedCrossRefGoogle Scholar
  122. Suzuki T, Shimizu Y, Furuhata E et al (2017) RUNX1 regulates site specificity of DNA demethylation by recruitment of DNA demethylation machineries in hematopoietic cells. Blood Adv 1:1699–1711PubMedPubMedCentralCrossRefGoogle Scholar
  123. Tahiliani M, Koh KP, Shen Y et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–935PubMedPubMedCentralCrossRefGoogle Scholar
  124. Tamanaha E, Guan S, Marks K et al (2016) Distributive processing by the iron(II)/alpha-ketoglutarate-dependent catalytic domains of the TET enzymes is consistent with epigenetic roles for oxidized 5-methylcytosine bases. J Am Chem Soc 138:9345–9348PubMedCrossRefGoogle Scholar
  125. Vakoc CR, Sachdeva MM, Wang H et al (2006) Profile of histone lysine methylation across transcribed mammalian chromatin. Mol Cell Biol 26:9185–9195PubMedPubMedCentralCrossRefGoogle Scholar
  126. Varley KE, Gertz J, Bowling KM et al (2013) Dynamic DNA methylation across diverse human cell lines and tissues. Genome Res 23:555–567PubMedPubMedCentralCrossRefGoogle Scholar
  127. Vella P, Scelfo A, Jammula S et al (2013) Tet proteins connect the O-linked N-acetylglucosamine transferase Ogt to chromatin in embryonic stem cells. Mol Cell 49:645–656PubMedCrossRefGoogle Scholar
  128. Vilkaitis G, Suetake I, Klimasauskas S et al (2005) Processive methylation of hemimethylated CpG sites by mouse Dnmt1 DNA methyltransferase. J Biol Chem 280:64–72PubMedCrossRefGoogle Scholar
  129. Vojta A, Dobrinic P, Tadic V et al (2016) Repurposing the CRISPR-Cas9 system for targeted DNA methylation. Nucleic Acids Res 44:5615–5628PubMedPubMedCentralCrossRefGoogle Scholar
  130. von Meyenn F, Iurlaro M, Habibi E et al (2016) Impairment of DNA methylation maintenance is the main cause of global demethylation in naive embryonic stem cells. Mol Cell 62:983CrossRefGoogle Scholar
  131. Wolfe SA, Nekludova L, Pabo CO (2000) DNA recognition by Cys2His2 zinc finger proteins. Annu Rev Biophys Biomol Struct 29:183–212PubMedCrossRefGoogle Scholar
  132. Xiong T, Meister GE, Workman RE et al (2017) Targeted DNA methylation in human cells using engineered dCas9-methyltransferases. Sci Rep 7:6732PubMedPubMedCentralCrossRefGoogle Scholar
  133. Xu GL, Bestor TH (1997) Cytosine methylation targetted to pre-determined sequences. Nat Genet 17:376–378PubMedCrossRefGoogle Scholar
  134. Xu Y, Xu C, Kato A et al (2012) Tet3 CXXC domain and dioxygenase activity cooperatively regulate key genes for Xenopus eye and neural development. Cell 151:1200–1213PubMedPubMedCentralCrossRefGoogle Scholar
  135. Xu C, Liu K, Lei M et al (2018) DNA sequence recognition of human CXXC domains and their structural determinants. Structure 26:85–95 e83PubMedCrossRefGoogle Scholar
  136. Yamazaki Y, Mann MR, Lee SS et al (2003) Reprogramming of primordial germ cells begins before migration into the genital ridge, making these cells inadequate donors for reproductive cloning. Proc Natl Acad Sci U S A 100:12207–12212PubMedPubMedCentralCrossRefGoogle Scholar
  137. Yang L, Rau R, Goodell MA (2015) DNMT3A in haematological malignancies. Nat Rev Cancer 15:152–165PubMedPubMedCentralCrossRefGoogle Scholar
  138. Zhang H, Zhang X, Clark E et al (2010a) TET1 is a DNA-binding protein that modulates DNA methylation and gene transcription via hydroxylation of 5-methylcytosine. Cell Res 20:1390–1393PubMedCrossRefGoogle Scholar
  139. Zhang Y, Jurkowska R, Soeroes S et al (2010b) Chromatin methylation activity of Dnmt3a and Dnmt3a/3L is guided by interaction of the ADD domain with the histone H3 tail. Nucleic Acids Res 38:4246–4253PubMedPubMedCentralCrossRefGoogle Scholar
  140. Zhang ZM, Lu R, Wang P et al (2018) Structural basis for DNMT3A-mediated de novo DNA methylation. Nature 554:387–391PubMedPubMedCentralCrossRefGoogle Scholar
  141. Ziller MJ, Muller F, Liao J et al (2011) Genomic distribution and inter-sample variation of non-CpG methylation across human cell types. PLoS Genet 7:e1002389PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.BioMed X Innovation CenterHeidelbergGermany
  2. 2.Abteilung BiochemieInstitut für Biochemie und Technische Biochemie, Universität StuttgartStuttgartGermany

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