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Vol. 113, No. 1-4, 2006
Issue release date: March 2006

Regulation of imprinted DNA methylation

Holmes R. · Soloway P.D.
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DNA methylation is an essential enzymatic modification in mammals. This common epigenetic mark occurs predominantly at the fifth carbon of cytosines within the palindromic dinucleotide 5′-CpG-3′. The majority of methylated CpGs are located within repetitive elements including centromeric repeats, satellite sequences and gene repeats encoding ribosomal RNAs. CpG islands, frequently located at the 5′ end of genes, are typically unmethylated. DNA methylation also occurs at imprinted genes which exhibit parent-of-origin-specific patterns of methylation and expression. Imprinted methylation at differentially methylated domains (DMDs) is one of the regulatory mechanisms controlling the allele-specific expression of imprinted genes. Proper control of DNA methylation is needed for normal development and loss of methylation control can contribute to initiation and progression of tumorigenesis (reviewed in Plass and Soloway, 2002). Because patterns of imprinted DNA methylation are highly reproducible, imprinted loci make useful models for studying regulation of DNA methylation and may provide insights into how this regulation goes awry in cancer. Here, we review what is currently known about the mechanisms regulating imprinted DNA methylation. We will focus on cis-acting DNA sequences, trans-acting protein factors and the possible involvement of RNAs in control of imprinted DNA methylation.

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  1. Aufsatz W, Mette MF, van der Winden J, Matzke M, Matzke AJ: HDA6, a putative histone deacetylase needed to enhance DNA methylation induced by double-stranded RNA. EMBO J 21:6832–6841 (2002).
  2. Bao N, Lye K-W, Barton MK: MicroRNA binding sites in Arabidopsis class III HD-ZIP mRNAs are required for methylation of the template chromosome. Dev Cell 7:653–662 (2004).
  3. Barlow DP, Stoger R, Herrmann BG, Saito K, Schweifer N: The mouse insulin-like growth factor type-2 receptor is imprinted and closely linked to the Tme locus. Nature 349:84–87 (1991).
  4. Bell AC, Felsenfeld G: Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene. Nature 405:482–485 (2000).
  5. 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).
  6. Bestor TH, Gundersen G, Kolsto AB, Prydz H: CpG islands in mammalian gene promoters are inherently resistant to de novo methylation. Genet Anal Tech Appl 9:48–53 (1992).
  7. Birger Y, Shemer R, Perk J, Razin A: The imprinting box of the mouse Igf2r gene. Nature 397:84–88 (1999).
  8. Bourc’his D, Xu GL, Lin CS, Bollman B, Bestor TH: Dnmt3L and the establishment of maternal genomic imprints. Science 294:2536–2539 (2001).
  9. Chan SW, Henderson IR, Jacobsen SE: Gardening the genome: DNA methylation in Arabidopsisthaliana. Nat Rev Genet 6:351–360 (2005).
  10. Chedin F, Lieber MR, Hsieh CL: The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a. Proc Natl Acad Sci USA 99:16916–16921 (2002).
  11. Chen T, Li E: Structure and function of eukaryotic DNA methyltransferases. Curr Top Dev Biol 60:55–89 (2004).
  12. Czermin B, Schotta G, Hulsmann BB, Brehm A, Becker PB, Reuter G, Imhof A: Physical and functional association of SU (VAR)3–9 and HDAC1 in Drosophila. EMBO Rep 2:915–919 (2001).
  13. Davis E, Caiment F, Tordoir, X, Cavaille J, Ferguson-Smith A, Cockett N, Georges M, Charlier C: RNAi-mediated allelic trans-interaction at the imprinted Rtl1/Peg11 locus. Curr Biol 15:743–749 (2005).
  14. 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).
  15. Du M, Beatty LG, Zhou W, Lew J, Schoenherr C, Weksberg R, Sadowski PD: Insulator and silencer sequences in the imprinted region of human chromosome 11p15.5. Hum Mol Genet 12:1927–1939 (2003).
  16. Fedoriw AM, Stein P, Svoboda P, Schultz RM, Bartolomei MS: Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting. Science 303:238–240 (2004).
  17. Freitag M, Hickey PC, Khlafallah TK, Read ND, Selker EU: HP1 is essential for DNA methylation in Neurospora. Mol Cell 13:427–434 (2004).
  18. Fromm M, Berg P: Transcription in vivo from SV40 early promoter deletion mutants without repression by large T antigen. J Mol Appl Genet 2:127–135 (1983).
  19. Gendrel AV, Lippman Z, Yordan C, Colot V, Martienssen RA: Dependence of heterochromatic histone H3 methylation patterns on the Arabidopsis gene DDM1. Science 297:1871–1873 (2002).
  20. Gibbons RJ, McDowell TL, Raman S, O’Rourke DM, Garrick D, Ayyub H, Higgs DR: Mutations in ATRX, encoding a SWI/SNF-like protein, cause diverse changes in the pattern of DNA methylation. Nat Genet 24:368–371 (2000).
  21. Grandjean V, O’Neill L, Sado T, Turner B, Ferguson-Smith A: Relationship between DNA methylation, histone H4 acetylation and gene expression in the mouse imprinted Igf2-H19 domain. FEBS Lett 488:165–169 (2001).
  22. Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levorse JM, Tilghman SM: CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 405:486–489 (2000).
  23. Hata K, Okano M, Lei H, Li E: Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 129:1983–1993 (2002).
  24. Herman H, Lu M, Anggraini M, Sikora A, Chang Y, Yoon BJ, Soloway PD: Trans allele methylation and paramutation-like effects in mice. Nat Genet 34:199–202 (2003).
  25. Hikichi T, Kohda T, Kaneko-Ishino T, Ishino F: Imprinting regulation of the murine Meg1/Grb10 and human GRB10 genes; roles of brain-specific promoters and mouse-specific CTCF-binding sites. Nucleic Acids Res 31:1398–1406 (2003).
  26. Jackson JP, Lindroth AM, Cao X, Jacobsen SE: Control of CpNpG DNA methylation by the KRYPTONITE histone H3 methyltransferase. Nature 416:556–560 (2002).
  27. Jeddeloh JA, Stokes TL, Richards EJ: Maintenance of genomic methylation requires a SWI2/SNF2-like protein. Nat Genet 22:94–97 (1999).
  28. Jones L, Ratcliff F, Baulcombe DC: RNA-directed transcriptional gene silencing in plants can be inherited independently of the RNA trigger and requires Met1 for maintenance. Curr Biol 11:747–757 (2001).
  29. Kanduri C, Pant V, Loukinov D, Pugacheva E, Qi CF, Wolffe A, Ohlsson R, Lobanenkov VV: Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive. Curr Biol 10:853–856 (2000).
  30. Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E, Sasaki H: Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature 429:900–903 (2004).
  31. Kantor B, Makedonski K, Green-Finberg Y, Shemer R, Razin A: Control elements within the PWS/ AS imprinting box and their function in the imprinting process. Hum Mol Genet 13:751–762 (2004).
  32. Kawasaki H, Taira K: Induction of DNA methylation and gene silencing by short interfering RNAs in human cells. Nature 431:211–217 (2004).
  33. Lee RC, Feinbaum RL, Ambros V: The C.elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854 (1993).
  34. Leff SE, Brannan CI, Reed ML, Ozcelik T, Francke U, Copeland NG, Jenkins NA: Maternal imprinting of the mouse Snrpn gene and conserved linkage homology with the human Prader-Willi syndrome region. Nat Genet 2:259–264 (1992).
  35. Lehnertz B, Ueda Y, Derijck AA, Braunschweig U, Perez-Burgos L, Kubicek S, Chen T, Li E, Jenuwein T, Peters AH: Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr Biol 13:1192–1200 (2003).
  36. Lewis A, Mitsuya K, Constancia M, Reik W: Tandem repeat hypothesis in imprinting: deletion of a conserved direct repeat element upstream of H19 has no effect on imprinting in the Igf2-H19 region. Mol Cell Biol 24:5650–5656 (2004a).
  37. Lewis A, Mitsuya K, Umlauf D, Smith P, Dean W, Walter J, Higgins M, Feil R, Reik W: Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation. Nat Genet 36:1291–1295 (2004b).
  38. Li E, Bestor TH, Jaenisch R: Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69:915–926 (1992).
  39. Li E, Beard C, Jaenisch R: Role for DNA methylation in genomic imprinting. Nature 366:362–365 (1993).
  40. Lin SP, Youngson N, Takada S, Seitz H, Reik W, Paulsen M, Cavaille J, Ferguson-Smith AC: Asymmetric regulation of imprinting on the maternal and paternal chromosomes at the Dlk1-Gtl2 imprinted cluster on mouse chromosome 12. Nat Genet 35:97–102 (2003).
  41. Lippman Z, Martienssen R: The role of RNA interference in heterochromatic silencing. Nature 431:364–370 (2004).
  42. Liu K, Wang YF, Cantemir C, Muller MT: Endogenous assays of DNA methyltransferases: Evidence for differential activities of DNMT1, DNMT2, and DNMT3 in mammalian cells in vivo. Mol Cell Biol 23:2709–2719 (2003).
  43. Loukinov DI, Pugacheva E, Vatolin S, Pack SD, Moon H, Chernukhin I, Mannan P, Larsson E, Kanduri C, Vostrov AA, et al: BORIS, a novel male germ-line-specific protein associated with epigenetic reprogramming events, shares the same 11-zinc-finger domain with CTCF, the insulator protein involved in reading imprinting marks in the soma. Proc Natl Acad Sci USA 99:6806–6811 (2002).
  44. Mager J, Montgomery ND, de Villena FP, Magnuson T: Genome imprinting regulated by the mouse Polycomb group protein Eed. Nat Genet 33:502–507 (2003).
  45. Malagnac F, Bartee L, Bender J: An Arabidopsis SET domain protein required for maintenance but not establishment of DNA methylation. EMBO J 21:6842–6852 (2002).
  46. Martienssen RA: Maintenance of heterochromatin by RNA interference of tandem repeats. Nat Genet 35:213–214 (2003).
  47. Miura A, Yonebayashi S, Watanabe K, Toyama T, Shimada H, Kakutani T: Mobilization of transposons by a mutation abolishing full DNA methylation in Arabidopsis. Nature 411:212–214 (2001).
  48. Morris KV, Chan SW-L, Jacobsen SE, Looney DJ: Small interfering RNA-induced transcriptional gene silencing in human cells. Science 305:1289–1292 (2004).
  49. Neumann B, Kubicka P, Barlow DP: Characteristics of imprinted genes. Nat Genet 9:12–13 (1995).
  50. 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).
  51. Okano M, Bell DW, Haber DA, Li E: DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99:247–257 (1999).
  52. Otte K, Choudhury D, Charalambous M, Engstrom W, Rozell B: A conserved structural element in horse and mouse IGF2 genes binds a methylation sensitive factor. Nucleic Acids Res 26:1605–1612 (1998).
  53. Pant V, Kurukuti S, Pugacheva E, Shamsuddin S, Mariano P, Renkawitz R, Klenova E, Lobanenkov V, Ohlsson R: Mutation of a single CTCF target site within the H19 imprinting control region leads to loss of Igf2 imprinting and complex patterns of de novo methylation upon maternal inheritance. Mol Cell Biol 24:3497–3504 (2004).
  54. Pearsall RS, Plass C, Romano MA, Garrick MD, Shibata H, Hayashizaki Y, Held WA: A direct repeat sequence at the Rasgrf1 locus and imprinted expression. Genomics 55:194–201 (1999).
  55. Plass C, Soloway PD: DNA methylation, imprinting and cancer. Eur J Hum Genet 10:6–16 (2002).
  56. Plass C, Shibata H, Kalcheva I, Mullins L, Kotelevtseva N, Mullins J, Kato R, Sasaki H, Hirotsune S, Okazaki Y, et al: Identification of Grf1 on mouse chromosome 9 as an imprinted gene by RLGS-M. Nat Genet 14:106–109 (1996).
  57. Rand E, Ben-Porath I, Keshet I, Cedar H: CTCF elements direct allele-specific undermethylation at the imprinted H19 locus. Curr Biol 14:1007–1012 (2004).
  58. Reale A, Matteis GD, Galleazzi G, Zampieri M, Caiafa P: Modulation of DNMT1 activity by ADP-ribose polymers. Oncogene 24:13–19 (2005).
  59. Reed MR, Riggs AD, Mann JR: Deletion of a direct repeat element has no effect on Igf2 and H19 imprinting. Mamm Genome 12:873–876 (2001).
  60. Reik W, Walter J: Evolution of imprinting mechanisms: the battle of the sexes begins in the zygote. Nat Genet 27:255–256 (2001).
  61. Sakai Y, Suetake I, Shinozaki F, Yamashina S, Tajima S: Co-expression of de novo DNA methyltransferases Dnmt3a2 and Dnmt3L in gonocytes of mouse embryos. Gene Expr Patterns 5:231–237 (2004).
  62. Scheid OM, Afsar K, Paszkowski J: Release of epigenetic gene silencing by trans-acting mutations in Arabidopsis. Proc Natl Acad Sci USA 95:632–637 (1998).
  63. Schoenherr CJ, Levorse JM, Tilghman SM: CTCF maintains differential methylation at the Igf2/H19 locus. Nat Genet 33:66–69 (2003).
  64. Seitz H, Royo H, Bortolin ML, Lin SP, Ferguson-Smith AC, Cavaille J: A large imprinted microRNA gene cluster at the mouse Dlk1-Gtl2 domain. Genome Res 14:1741–1748 (2004).
  65. Selker EU, Stevens JN: DNA methylation at asymmetric sites is associated with numerous transition mutations. Proc Natl Acad Sci USA 82:8114–8118 (1985).
  66. Shibata H, Yoda Y, Kato R, Ueda T, Kamiya M, Hiraiwa N, Yoshiki A, Plass C, Pearsall RS, Held WA, et al: A methylation imprint mark in the mouse imprinted gene Grf1/Cdc25Mm locus shares a common feature with the U2afbp-rs gene: an association with a short tandem repeat and a hypermethylated region. Genomics 49:30–37 (1998).
  67. Singer T, Yordan C, Martienssen RA: Robertson’s Mutator transposons in A.thaliana are regulated by the chromatin-remodeling gene Decrease in DNA Methylation (DDM1). Genes Dev 15:591–602 (2001).
  68. Stadnick MP, Pieracci FM, Cranston MJ, Taksel E, Thorvaldsen JL, Bartolomei MS: Role of a 461-bp G-rich repetitive element in H19 transgene imprinting. Dev Genes Evol 209:239–248 (1999).
  69. Suetake I, Shinozaki F, Miyagawa J, Takeshima H, Tajima S: DNMT3L stimulates the DNA methylation activity of Dnmt3a and Dnmt3b through a direct interaction. J Biol Chem 279:27816–27823 (2004).
  70. Takada S, Paulsen M, Tevendale M, Tsai CE, Kelsey G, Cattanach BM, Ferguson-Smith AC: Epigenetic analysis of the Dlk1-Gtl2 imprinted domain on mouse chromosome 12: implications for imprinting control from comparison with Igf2-H19. Hum Mol Genet 11:77–86 (2002).
  71. Tamaru H, Selker EU: A histone H3 methyltransferase controls DNA methylation in Neurosporacrassa. Nature 414:277–283 (2001).
  72. Tamaru H, Zhang X, McMillen D, Singh PB, Nakayama J, Grewal SI, Allis CD, Cheng X, Selker EU: Trimethylated lysine 9 of histone H3 is a mark for DNA methylation in Neurosporacrassa. Nat Genet 34:75–79 (2003).
  73. Thorvaldsen JL, Duran KL, Bartolomei MS: Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2. Genes Dev 12:3693–3702 (1998).
  74. Thorvaldsen JL, Mann MR, Nwoko O, Duran KL, Bartolomei MS: Analysis of sequence upstream of the endogenous H19 gene reveals elements both essential and dispensable for imprinting. Mol Cell Biol 22:2450–2462 (2002).
  75. Tufarelli C, Stanley JA, Garrick D, Sharpe JA, Ayyub H, Wood WG, Higgs DR: Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nat Genet 34:157–165 (2003).
  76. Umlauf D, Goto Y, Cao R, Cerqueira F, Wagschal A, Zhang Y, Feil R: Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes. Nat Genet 36:1296–1300 (2004).
  77. van der Vlag J, Otte AP: Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nat Genet 23:474–478 (1999).
  78. Vongs A, Kakutani T, Martienssen RA, Richards EJ: Arabidopsisthaliana DNA methylation mutants. Science 260:1926–1928 (1993).
  79. Wang J, Mager J, Chen Y, Schneider E, Cross JC, Nagy A, Magnuson T: Imprinted X inactivation maintained by a mouse Polycomb group gene. Nat Genet 28:371–375 (2001).
  80. Wassenegger M, Heimes S, Riedel L, Sanger HL: RNA-directed de novo methylation of genomic sequences in plants. Cell 76:567–576 (1994).
  81. Webster KE, O’Bryan MK, Fletcher S, Crewther PE, Aapola U, Craig J, Harrison DK, Aung H, Phutikanit N, Lyle R, et al: Meiotic and epigenetic defects in Dnmt3L-knockout mouse spermatogenesis. Proc Natl Acad Sci USA 102:4068–4073 (2005).
  82. Wutz A, Smrzka OW, Schweifer N, Schellander K, Wagner EF, Barlow DP: Imprinted expression of the Igf2r gene depends on an intronic CpG island. Nature 389:745–749 (1997).
  83. Yoder JA, Bestor TH: A candidate mammalian DNA methyltransferase related to pmt1p of fission yeast. Hum Mol Genet 7:279–284 (1998).
  84. Yoon BJ, Herman H, Sikora A, Smith LT, Plass C, Soloway PD: Regulation of DNA methylation of Rasgrf1. Nat Genet 30:92–96 (2002).
  85. Yu W, Ginjala V, Pant V, Chernukhin I, Whitehead J, Docquier F, Farrar D, Tavoosidana G, Mukhopadhyay R, Kanduri C, et al: Poly (ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation. Nat Genet 36:1105–1110 (2004).

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