Display options
Share it on

Epigenetics Chromatin. 2015 Jul 21;8:24. doi: 10.1186/s13072-015-0016-6. eCollection 2015.

Epigenetic regulatory functions of DNA modifications: 5-methylcytosine and beyond.

Epigenetics & chromatin

Achim Breiling, Frank Lyko

Affiliations

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

PMID: 26195987 PMCID: PMC4507326 DOI: 10.1186/s13072-015-0016-6

Abstract

The chemical modification of DNA bases plays a key role in epigenetic gene regulation. While much attention has been focused on the classical epigenetic mark, 5-methylcytosine, the field garnered increased interest through the recent discovery of additional modifications. In this review, we focus on the epigenetic regulatory roles of DNA modifications in animals. We present the symmetric modification of 5-methylcytosine on CpG dinucleotide as a key feature, because it permits the inheritance of methylation patterns through DNA replication. However, the distribution patterns of cytosine methylation are not conserved in animals and independent molecular functions will likely be identified. Furthermore, the discovery of enzymes that catalyse the hydroxylation of 5-methylcytosine to 5-hydroxymethylcytosine not only identified an active demethylation pathway, but also a candidate for a new epigenetic mark associated with activated transcription. Most recently, N6-methyladenine was described as an additional eukaryotic DNA modification with epigenetic regulatory potential. Interestingly, this modification is also present in genomes that lack canonical cytosine methylation patterns, suggesting independent functions. This newfound diversity of DNA modifications and their potential for combinatorial interactions indicates that the epigenetic DNA code is substantially more complex than previously thought.

Keywords: 5-Hydroxymethylcytosine; 5-Methylcytosine; Chromatin; DNA demethylation; DNA methylation; DNA modification; Epigenetic marks; Gene regulation; Inheritance; Modified DNA bases; N6-methyladenine

References

  1. Cell. 2015 May 7;161(4):893-906 - PubMed
  2. Genes Dev. 2014 Oct 1;28(19):2103-19 - PubMed
  3. Genome Biol. 2012 Aug 17;13(8):R69 - PubMed
  4. Nature. 2015 Feb 19;518(7539):317-30 - PubMed
  5. Cell. 2015 May 7;161(4):879-92 - PubMed
  6. PLoS One. 2010 Dec 23;5(12):e15367 - PubMed
  7. Mol Cell. 2014 Oct 23;56(2):286-97 - PubMed
  8. Science. 2011 Sep 2;333(6047):1303-7 - PubMed
  9. Proc Natl Acad Sci U S A. 2010 May 11;107(19):8689-94 - PubMed
  10. Dev Cell. 2013 Feb 11;24(3):310-23 - PubMed
  11. Genes Dev. 2011 Dec 1;25(23):2436-52 - PubMed
  12. Curr Opin Genet Dev. 2014 Apr;25:85-92 - PubMed
  13. Science. 2010 Jul 23;329(5990):444-8 - PubMed
  14. Nucleic Acids Res. 2012 Sep 1;40(17):8255-65 - PubMed
  15. Cold Spring Harb Perspect Biol. 2014 Dec 01;6(12):a019315 - PubMed
  16. Science. 2013 Aug 9;341(6146):1237905 - PubMed
  17. Cell. 2013 May 23;153(5):1134-48 - PubMed
  18. Nat Genet. 2015 May;47(5):469-78 - PubMed
  19. Cell Stem Cell. 2014 Apr 3;14(4):512-22 - PubMed
  20. Bioessays. 2006 Mar;28(3):309-15 - PubMed
  21. Annu Rev Biochem. 2005;74:481-514 - PubMed
  22. Cell. 1999 Oct 29;99(3):247-57 - PubMed
  23. Cell Stem Cell. 2011 Feb 4;8(2):200-13 - PubMed
  24. Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14566-71 - PubMed
  25. Nat Cell Biol. 2015 May;17 (5):545-57 - PubMed
  26. Cell. 2011 Dec 23;147(7):1498-510 - PubMed
  27. Nucleic Acids Res. 2014 Jun;42(11):6956-71 - PubMed
  28. Nat Rev Genet. 2013 Mar;14(3):204-20 - PubMed
  29. Nat Biotechnol. 2011 Jan;29(1):68-72 - PubMed
  30. Genome Biol. 2015 Jun 02;16:115 - PubMed
  31. Trends Biochem Sci. 2006 Feb;31(2):89-97 - PubMed
  32. Nature. 1993 Nov 25;366(6453):362-5 - PubMed
  33. Nat Struct Mol Biol. 2014 Nov;21(11):949-54 - PubMed
  34. PLoS Biol. 2010 Nov 02;8(11):e1000506 - PubMed
  35. Genes Dev. 2011 Apr 1;25(7):679-84 - PubMed
  36. Cell. 2013 May 23;153(5):1149-63 - PubMed
  37. Blood. 2011 Oct 27;118(17):4509-18 - PubMed
  38. Nature. 2015 Jun 4;522(7554):89-93 - PubMed
  39. Cell. 2015 Mar 12;160(6):1049-59 - PubMed
  40. Science. 2011 Sep 2;333(6047):1300-3 - PubMed
  41. Nat Rev Mol Cell Biol. 2013 Jun;14(6):341-56 - PubMed
  42. Curr Opin Cell Biol. 2011 Jun;23(3):258-65 - PubMed
  43. Cell Rep. 2012 Nov 29;2(5):1411-24 - PubMed
  44. Curr Opin Genet Dev. 2012 Apr;22(2):156-63 - PubMed
  45. Proc Natl Acad Sci U S A. 2013 May 21;110(21):8627-31 - PubMed
  46. Cell. 2011 Jul 8;146(1):67-79 - PubMed
  47. Genome Res. 2014 May;24(5):821-30 - PubMed
  48. Cell Stem Cell. 2011 Aug 5;9(2):166-75 - PubMed
  49. Nat Chem Biol. 2014 Jul;10(7):574-81 - PubMed
  50. Cell. 2007 Feb 23;128(4):693-705 - PubMed
  51. Cell. 2013 Feb 28;152(5):1146-59 - PubMed
  52. Epigenetics. 2013 Feb;8(2):131-7 - PubMed
  53. Nat Neurosci. 2014 Feb;17(2):215-22 - PubMed
  54. Nature. 2015 Apr 9;520(7546):243-7 - PubMed
  55. Genes Dev. 1996 Aug 15;10(16):1991-2002 - PubMed
  56. Genome Biol. 2013;14(10):R119 - PubMed
  57. Cell. 2013 Apr 25;153(3):692-706 - PubMed
  58. Nat Rev Genet. 2012 May 29;13(7):484-92 - PubMed
  59. Nat Neurosci. 2011 Oct 30;14(12):1607-16 - PubMed
  60. Curr Opin Plant Biol. 2011 Apr;14(2):179-86 - PubMed
  61. Nature. 2010 Aug 26;466(7310):1129-33 - PubMed
  62. Science. 2009 May 15;324(5929):929-30 - PubMed
  63. FEBS Lett. 2006 May 29;580(13):3179-84 - PubMed
  64. Nature. 2011 Sep 04;477(7366):606-10 - PubMed
  65. Nat Chem. 2014 Dec;6(12):1049-55 - PubMed
  66. Cell. 2015 May 7;161(4):868-78 - PubMed
  67. Dev Cell. 2014 Apr 14;29(1):102-11 - PubMed
  68. Microbiol Mol Biol Rev. 2006 Sep;70(3):830-56 - PubMed
  69. Cell. 2012 Dec 21;151(7):1417-30 - PubMed
  70. Nature. 2007 May 24;447(7143):396-8 - PubMed
  71. Nature. 2009 Nov 19;462(7271):315-22 - PubMed
  72. Mol Cell. 2013 Nov 7;52(3):291-302 - PubMed
  73. Cell. 2013 Apr 25;153(3):678-91 - PubMed
  74. Biochem J. 1972 Feb;126(4):781-90 - PubMed
  75. Cell. 1992 Jun 12;69(6):915-26 - PubMed
  76. Nat Genet. 1998 Oct;20(2):116-7 - PubMed
  77. Nat Commun. 2012 May 08;3:818 - PubMed
  78. Science. 2008 Mar 28;319(5871):1827-30 - PubMed
  79. Prog Mol Biol Transl Sci. 2011;101:25-104 - PubMed
  80. Cell. 2012 Feb 17;148(4):816-31 - PubMed
  81. Science. 2009 May 15;324(5929):930-5 - PubMed
  82. Cell Rep. 2013 Feb 21;3(2):291-300 - PubMed
  83. Science. 2010 May 14;328(5980):916-9 - PubMed
  84. Nat Rev Genet. 2011 Feb;12(2):123-35 - PubMed
  85. Curr Opin Plant Biol. 2012 Nov;15(5):523-9 - PubMed

Publication Types