Mapping the epigenome — impact for toxicology

  • Jennifer Marlowe
  • Soon-Siong Teo
  • Salah-Dine Chibout
  • François Pognan
  • Jonathan Moggs
Part of the Experientia Supplementum book series (EXS, volume 99)


Recent advances in technological approaches for mapping and characterizing the epigenome are generating a wealth of new opportunities for exploring the relationship between epigenetic modifications, human disease and the therapeutic potential of pharmaceutical drugs. While the best examples for xenobiotic-induced epigenetic perturbations come from the field of non-genotoxic carcinogenesis, there is growing evidence for the relevance of epigenetic mechanisms associated with a wide range of disease areas and drug targets. The application of epigenomic profiling technologies to drug safety sciences has great potential for providing novel insights into the molecular basis of long-lasting cellular perturbations including increased susceptibility to disease and/or toxicity, memory of prior immune stimulation and/or drug exposure, and transgenerational effects.


Circulate Tumor Cell B6C3F1 Mouse Restriction Landmark Genomic Scan Epigenomic Profile Human Epigenome Project 


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  1. 1.
    Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6: 597–610PubMedCrossRefGoogle Scholar
  2. 2.
    Eckhardt F, Beck S, Gut IG, Berlin K (2004) Future potential of the Human Epigenome Project. Expert Rev Mol Diagn 4: 609–618PubMedCrossRefGoogle Scholar
  3. 3.
    Rakyan VK, Hildmann T, Novik KL, Lewin J, Tost J, Cox AV, Andrews TD, Howe KL, Otto T, Olek A et al (2004) DNA methylation profiling of the human major histocompatibility complex: A pilot study for the Human Epigenome Project. PLoS Biology 2: e405PubMedCrossRefGoogle Scholar
  4. 4.
    Eckhardt F, Lewin J, Cortese R, Rakyan VK, Attwood J, Burger M, Burton J, Cox TV, Davies R, Down TA et al (2006) DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet 38: 1378–1385PubMedCrossRefGoogle Scholar
  5. 5.
    Weber M, Davies JJ, Wittig D, Oakeley EJ, Haase M, Lam WL, Schübeler D (2005) Chromosomewide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat Genet 37: 853–862PubMedCrossRefGoogle Scholar
  6. 6.
    Weber M, Hellmann I, Stadler MB, Ramos L, Paabo S, Rebhan M, Schübeler D (2007) Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat Genet 39: 457–466PubMedCrossRefGoogle Scholar
  7. 7.
    Tyson FL, Heindel J (2005) Environmental influences on epigenetic regulation. Environ Health Perspect 113: A839Google Scholar
  8. 8.
    Akhtar A, Cavalli G (2005) The Epigenome Network of Excellence. PLoS Biology 3: e177PubMedCrossRefGoogle Scholar
  9. 9.
    Grunau C, Renault E, Rosenthal A, Roizes G (2001) MethDB-A public database for DNA methylation data. Nucleic Acids Res 29: 270–274PubMedCrossRefGoogle Scholar
  10. 10.
    Mariño-Ramírez L, Hsu B, Baxevanis AD, Landsman D (2006) The histone database: A comprehensive resource for histones and histone fold-containing proteins. Proteins 62: 838–842PubMedCrossRefGoogle Scholar
  11. 11.
    Nafee TM, Farrell WE, Carroll WD, Fryer AA, Ismail KMK (2008) Epigenetic control of fet al gene expression. BJOG 115: 158–168PubMedCrossRefGoogle Scholar
  12. 12.
    Morison IM, Paton CJ, Cleverley SD (2001) The imprinted gene and parent-of-origin effect database. Nucleic Acids Res 29: 275–276PubMedCrossRefGoogle Scholar
  13. 13.
    Nicholls RD, Knepper JL (2001) Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes. Annu Rev Genomics Hum Genet 2: 153–175PubMedCrossRefGoogle Scholar
  14. 14.
    Tycko B (1997) DNA methylation in genomic imprinting. Mutat Res 386: 131–140PubMedCrossRefGoogle Scholar
  15. 15.
    Esteller M (2007) Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8: 286–298PubMedCrossRefGoogle Scholar
  16. 16.
    Clark SJ, Statham A, Stirzaker C, Molloy PL, Frommer M (2006) DNA methylation: Bisulphite modification and analysis. Nat Protoc 1: 2353–2364PubMedCrossRefGoogle Scholar
  17. 17.
    Fraga MF, Esteller M (2002) DNA methylation: A profile of methods and applications. Biotechniques 33: 632–649PubMedGoogle Scholar
  18. 18.
    Grigg G, Clark S (1994) Sequencing 5-methylcytosine residues in genomic DNA. Bioessays 16: 431–436PubMedCrossRefGoogle Scholar
  19. 19.
    Frommer M, McDonald LE, Millar DS, Collis CM, Watt F, Grigg GW, Molloy PL, Paul CL (1992) A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci USA 89: 1827–1831PubMedCrossRefGoogle Scholar
  20. 20.
    Clark SJ, Harrison J, Paul CL, Frommer M (1994) High sensitivity mapping of methylated cytosines. Nucleic Acids Res 22: 2990–2997PubMedCrossRefGoogle Scholar
  21. 21.
    Clark SJ, Millar DS, Molloy PL (2003) Bisulfite methylation analysis of tumor suppressor genes in prostate cancer from fresh and archival tissue samples. Methods Mol Med 81: 219–240PubMedGoogle Scholar
  22. 22.
    Costello JF, Fruhwald MC, Smiraglia DJ, Rush LJ, Robertson GP, Gao X, Wright FA, Feramisco JD, Peltomaki P, Lang JC et al (2000) Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat Genet 24: 132–138PubMedCrossRefGoogle Scholar
  23. 23.
    Welsh J, McClelland M (1990) Fingerprinting genomes using PCR with arbitrary primers. Nucleic Acids Res 18: 7213–7218PubMedCrossRefGoogle Scholar
  24. 24.
    Gonzalgo ML, Liang G, Spruck CH, III, Zingg JM, Rideout WM III, Jones PA (1997) Identification and characterization of differentially methylated regions of genomic DNA by methylation-sensitive arbitrarily primed PCR. Cancer Res 57: 594–599PubMedGoogle Scholar
  25. 25.
    Toyota M, Ho C, Ahuja N, Jair KW, Li Q, Ohe-Toyota M, Baylin SB, Issa JP (1999) Identification of differentially methylated sequences in colorectal cancer by methylated CpG island amplification. Cancer Res 59: 2307–2312PubMedGoogle Scholar
  26. 26.
    Frigola J, Ribas M, Risques RA, Peinado MA (2002) Methylome profiling of cancer cells by amplification of inter-methylated sites (AIMS). Nucleic Acids Res 30: e28PubMedCrossRefGoogle Scholar
  27. 27.
    Eads CA, Danenberg KDKK, Saltz LB, Blake C, Shibata D, Danenberg PV, Laird PW (2000) MethyLight: A high-throughput assay to measure DNA methylation. Nucleic Acids Res 28: e32PubMedCrossRefGoogle Scholar
  28. 28.
    Trinh BN, Long TI, Laird PW (2001) DNA Methylation analysis by MethyLight technology. Methods 25: 456–462PubMedCrossRefGoogle Scholar
  29. 29.
    Uhlmann K, Brinckmann A, Toliat MR, Ritter H, Nuernberg P (2002) Evaluation of a potential epigenetic biomarker by quantitative methyl-single nucleotide polymorphism analysis. Electrophoresis 23: 4072–4079PubMedCrossRefGoogle Scholar
  30. 30.
    Tost J, Gut IG (2007) DNA methylation analysis by pyrosequencing. Nat Protoc 2: 2265–2275PubMedCrossRefGoogle Scholar
  31. 31.
    Wong HL, Byun HM, Kwan JM, Campan M, Ingles SA, Laird PW, Yang AS (2006) Rapid and quantitative method of allele-specific DNA methylation analysis. Biotechniques 41: 734–739PubMedCrossRefGoogle Scholar
  32. 32.
    Yang AS, Estecio MRH, Doshi K, Kondo Y, Tajara EH, Issa JP (2004) A simple method for estimating global DNA methylation using bisulfite PCR of repetitive DNA elements. Nucleic Acids Res 32: e38PubMedCrossRefGoogle Scholar
  33. 33.
    Karimi M, Johansson S, Stach D, Corcoran M, Grander D, Schalling M, Bakalkin G, Lyko F, Larsson C, Ekstrom TJ (2006) LUMA (LUminometric Methylation Assay)-A high throughput method to the analysis of genomic DNA methylation. Exp Cell Res 312: 1989–1995PubMedCrossRefGoogle Scholar
  34. 34.
    Matarazzo MR, Lembo F, Angrisano T, Ballestar E, Ferraro M, Pero R, De Bonis ML, Bruni CB, Esteller M, D’Esposito M, Chiariotti L (2004) In vivo analysis of DNA methylation patterns recognized by specific proteins: Coupling ChIP and bisulfite analysis. Biotechniques 37: 666–673PubMedGoogle Scholar
  35. 35.
    Jacinto FV, Ballestar E, Esteller M (2008) Methyl-DNA immunoprecipitation (MeDIP): Hunting down the DNA methylome. Biotechniques 44: 35–43PubMedCrossRefGoogle Scholar
  36. 36.
    Buck MJ, Lieb JD (2004) ChIP-chip: Considerations for the design, analysis, and application of genome-wide chromatin immunoprecipitation experiments. Genomics 83: 349–360PubMedCrossRefGoogle Scholar
  37. 37.
    Jacinto FV, Ballestar E, Ropero S, Esteller M (2007) Discovery of epigenetically silenced genes by methylated DNA immunoprecipitation in colon cancer cells. Cancer Res 67: 11481–11486PubMedCrossRefGoogle Scholar
  38. 38.
    Milutinovic S, D’Alessio AC, Detich N, Szyf M (2007) Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes. Carcinogenesis 28: 560–571PubMedCrossRefGoogle Scholar
  39. 39.
    Gebhard C, Schwarzfischer L, Pham TH, Schilling E, Klug M, Andreesen R, Rehli M (2006) Genome-wide profiling of CpG methylation identifies novel targets of aberrant hypermethylation in myeloid leukemia. Cancer Res 66: 6118–6128PubMedCrossRefGoogle Scholar
  40. 40.
    Wardle FC, Odom DT, Bell GW, Yuan B, Danford TW, Wiellette EL, Herbolsheimer E, Sive HL, Young RA, Smith JC (2006) Zebrafish promoter microarrays identify actively transcribed embryonic genes. Genome Biol 7: R71PubMedCrossRefGoogle Scholar
  41. 41.
    Wilson IM, Davies JJ, Weber M, Brown CJ, Alvarez CE, MacAulay C, Schübeler D, Lam WL (2006) Epigenomics: Mapping the methylome. Cell Cycle 5: 155–158PubMedGoogle Scholar
  42. 42.
    Galasinski SC, Resing KA, Ahn NG (2003) Protein mass analysis of histones. Methods 31: 3–11PubMedCrossRefGoogle Scholar
  43. 43.
    Smith CM, Haimberger ZW, Johnson CO, Wolf AJ, Gafken PR, Zhang Z, Parthun MR, Gottschling DE (2002) Heritable chromatin structure: Mapping “memory” in histones H3 and H4. Proc Natl Acad Sci USA 99: 16454–16461PubMedCrossRefGoogle Scholar
  44. 44.
    Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K et al (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet 37: 391–400PubMedCrossRefGoogle Scholar
  45. 45.
    Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M, Kurdistani SK (2005) Global histone modification patterns predict risk of prostate cancer recurrence. Nature 435: 1262–1266PubMedCrossRefGoogle Scholar
  46. 46.
    Bernstein BE, Humphrey EL, Long Liu C, Schreiber SL (2004) The use of chromatin immunoprecipitation assays in genome-wide analyses of histone modifications. Methods Enzymol 376: 349–360PubMedCrossRefGoogle Scholar
  47. 47.
    Lippman Z, Gendrel AV, Black M, Vaughn MW, Dedhia N, McCombie WR, Lavine K, Mittal V, May B, Kasschau KD et al (2004) Role of transposable elements in heterochromatin and epigenetic control. Nature 430: 471–476PubMedCrossRefGoogle Scholar
  48. 48.
    Bernstein BE, Kamal M, Lindblad-Toh K, Bekiranov S, Bailey DK, Huebert DJ, McMahon S, Karlsson EK, Kulbokas EJ, Gingeras TR et al (2005) Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120: 169–181PubMedCrossRefGoogle Scholar
  49. 49.
    Martens JHA, O’sullivan RJ, Braunschweig U, Opravil S, Radolf M, Steinlein P, Jenuwein T (2005) The profile of repeat-associated histone lysine methylation states in the mouse epigenome. EMBO J 24: 800–812PubMedCrossRefGoogle Scholar
  50. 50.
    Schübeler D, MacAlpine DM, Scalzo D, Wirbelauer C, Kooperberg C, van Leeuwen F, Gottschling DE, O’Neill LP, Turner BM, Delrow J et al (2004) The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote. Genes Dev 18: 1263–1271PubMedCrossRefGoogle Scholar
  51. 51.
    Kurdistani SK, Tavazoie S, Grunstein M (2004) Mapping global histone acetylation patterns to gene expression. Cell 117: 721–733PubMedCrossRefGoogle Scholar
  52. 52.
    Weinhold B (2006) Epigenetics: The science of change. Environ Health Perspect 114: A160–A167PubMedGoogle Scholar
  53. 53.
    Bombail V, Moggs JG, Orphanides G (2004) Perturbation of epigenetic status by toxicants. Toxicol Lett 149: 51–58PubMedCrossRefGoogle Scholar
  54. 54.
    Hitchins MP, Wong JJL, Suthers G, Suter CM, Martin DIK, Hawkins NJ, Ward RL (2007) Inheritance of a cancer-associated MLH1 germ-line epimutation. N Engl J Med 356: 697–705PubMedCrossRefGoogle Scholar
  55. 55.
    Jirtle RL, Skinner MK (2007) Environmental epigenomics and disease susceptibility. Nat Rev Genet 8: 253–262PubMedCrossRefGoogle Scholar
  56. 56.
    Reamon-Buettner SM, Borlak J (2007) A new paradigm in toxicology and teratology: Altering gene activity in the absence of DNA sequence variation. Reprod Toxicol 24: 20–30PubMedCrossRefGoogle Scholar
  57. 57.
    Rakyan VK, Blewitt ME, Druker R, Preis JI, Whitelaw E (2002) Metastable epialleles in mammals. Trends Genet 18: 348–351PubMedCrossRefGoogle Scholar
  58. 58.
    Dolinoy DC, Jirtle RL (2008) Environmental epigenomics in human health and disease. Environ Mol Mutagen 49: 4–8PubMedCrossRefGoogle Scholar
  59. 59.
    Dolinoy DC, Weidman JR, Jirtle RL (2007) Epigenetic gene regulation: Linking early developmental environment to adult disease. Reprod Toxicol 23: 297–307PubMedCrossRefGoogle Scholar
  60. 60.
    Feinberg AP, Ohlsson R, Henikoff S (2006) The epigenetic progenitor origin of human cancer. Nat Rev Genet 7: 21–33PubMedCrossRefGoogle Scholar
  61. 61.
    Baylin SB, Ohm JE (2006) Epigenetic gene silencing in cancer-A mechanism for early oncogenic pathway addiction? Nat Rev Cancer 6: 107–116PubMedCrossRefGoogle Scholar
  62. 62.
    Derks S, Postma C, Moerkerk PTM, van den Bosch SM, Carvalho B, Hermsen MAJA, Giaretti W, Herman JG, Weijenberg MP, de Bruïne AP et al (2006) Promoter methylation precedes chromosomal alterations in colorectal cancer development. Cell Oncol 28: 247–257PubMedGoogle Scholar
  63. 63.
    Kang GH, Lee S, Kim JS, Jung HY (2003) Profile of aberrant CpG island methylation along the multistep pathway of gastric carcinogenesis. Lab Invest 83: 635–641PubMedGoogle Scholar
  64. 64.
    Suzuki H, Gabrielson E, Chen W, Anbazhagan R, van Engeland M, Weijenberg MP, Herman JG, Baylin SB (2002) A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer. Nat Genet 31: 141–149PubMedCrossRefGoogle Scholar
  65. 65.
    Akiyama Y,Watkins N, Suzuki H, Jair KW, van Engeland M, Esteller M, Sakai H, Ren CY, Yuasa Y, Herman JG, Baylin SB (2003) GATA-4 and GATA-5 transcription factor genes and potential downstream antitumor target genes are epigenetically silenced in colorectal and gastric cancer. Mol Cell Biol 23: 8429–8439PubMedCrossRefGoogle Scholar
  66. 66.
    Rhee I, Bachman KE, Park BH, Jair KW, Yen RWC, Schuebel KE, Cui H, Feinberg AP, Lengauer C, Kinzler KW et al (2002) DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 416: 552–556PubMedCrossRefGoogle Scholar
  67. 67.
    Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW et al (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95: 6870–6875PubMedCrossRefGoogle Scholar
  68. 68.
    Bachman KE, Park BH, Rhee I, Rajagopalan H, Herman JG, Baylin SB, Kinzler KW, Vogelstein B (2003) Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 3: 89–95PubMedCrossRefGoogle Scholar
  69. 69.
    Suzuki H, Watkins DN, Jair KW, Schuebel KE, Markowitz SD, Dong Chen W, Pretlow TP, Yang B, Akiyama Y, van Engeland M et al (2004) Epigenetic inactivation of SFRP genes allows consti284 J. Marlowe et al. tutive WNT signaling in colorectal cancer. Nat Genet 36: 417–422PubMedCrossRefGoogle Scholar
  70. 70.
    Wales MM, Biel MA, Deiry WE, Nelkin BD, Issa JP, Cavenee WK, Kuerbitz SJ, Baylin SB (1995) P53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3. Nat Med 1: 570–577PubMedCrossRefGoogle Scholar
  71. 71.
    Chen W, Cooper TK, Zahnow CA, Overholtzer M, Zhao Z, Ladanyi M, Karp JE, Gokgoz N, Wunder JS, Andrulis IL et al (2004) Epigenetic and genetic loss of Hic1 function accentuates the role of p53 in tumorigenesis. Cancer Cell 6: 387–398PubMedCrossRefGoogle Scholar
  72. 72.
    Veigl ML, Kasturi L, Olechnowicz J, Ma A, Lutterbaugh JD, Periyasamy S, Li GM, Drummond J, Modrich PL, Sedwick WD, Markowitz SD (1998) Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci USA 95: 8698–8702PubMedCrossRefGoogle Scholar
  73. 73.
    Choi IS, Wu TT (2005) Epigenetic alterations in gastric carcinogenesis. Cell Res 15: 247–254PubMedCrossRefGoogle Scholar
  74. 74.
    Mittag F, Kuester D, Vieth M, Peters B, Stolte B, Roessner A, Schneider-Stock R (2006) DAPK promotor methylation is an early event in colorectal carcinogenesis. Cancer Lett 240: 69–75PubMedCrossRefGoogle Scholar
  75. 75.
    Wendt MK, Johanesen PA, Kang-Decker N, Binion DG, Shah V, Dwinell MB (2006) Silencing of epithelial CXCL12 expression by DNA hypermethylation promotes colonic carcinoma metastasis. Oncogene 25: 4986–4997PubMedCrossRefGoogle Scholar
  76. 76.
    Oue N, Mitani Y, Motoshita J, Matsumura S, Yoshida K, Kuniyasu H, Nakayama H, Yasui W (2006) Accumulation of DNA methylation is associated with tumor stage in gastric cancer. Cancer 106: 1250–1259PubMedCrossRefGoogle Scholar
  77. 77.
    To KF, Leung WK, Lee TL, Yu J, Tong JHM, Chan MWY, Ng EKW, Chung SCS, Sung JJY (2002) Promoter hypermethylation of tumor-related genes in gastric intestinal metaplasia of patients with and without gastric cancer. Int J Cancer 102: 623–628PubMedCrossRefGoogle Scholar
  78. 78.
    Dolinoy DC, Weidman JR, Waterland RA, Jirtle RL (2006) Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fet al epigenome. Environ Health Perspect 114: 567–572PubMedCrossRefGoogle Scholar
  79. 79.
    Ho SM, Tang WY, Belmonte de Frausto J, Prins GS (2006) Developmental exposure to estradiol and bisphenol A increases susceptibility to prostate carcinogenesis and epigenetically regulates phosphodiesterase type 4 variant 4. Cancer Res 66: 5624–5632PubMedCrossRefGoogle Scholar
  80. 80.
    Watson RE, Goodman JI (2002) Epigenetics and DNA methylation come of age in toxicology. Toxicol Sci 67: 11–16PubMedGoogle Scholar
  81. 81.
    Pogribny IP, Tryndyak VP, Woods C, Witt SE, Rusyn I (2007) Epigenetic effects of the continuous exposure to peroxisome proliferator WY-14,643 in mouse liver are dependent upon peroxisome proliferator activated receptor-a. Mutat Res 625: 62–71PubMedGoogle Scholar
  82. 82.
    Phillips JM, Yamamoto Y, Negishi M, Maronpot RR, Goodman JI (2007) Orphan nuclear receptor constitutive active/androstane receptor-mediated alterations in DNA methylation during phenobarbital promotion of liver tumorigenesis. Toxicol Sci 96: 72–82PubMedCrossRefGoogle Scholar
  83. 83.
    Ray JS, Harbison ML, McClain RM, Goodman JI (1994) Alterations in the methylation status and expression of the raf oncogene in phenobarbital-induced and spontaneous B6C3F1 mouse live tumors. Mol Carcinog 9: 155–166PubMedCrossRefGoogle Scholar
  84. 84.
    Denda A, Tang Q, Endoh T, Tsujiuchi T, Horiguchi K, Noguchi O, Mizumoto Y, Nakae D, Konishi Y (1994) Prevention by acetylsailcylic acid of liver cirrhosis and carcinogenesis as well as generations of 8-hydroxydeoxyguanosine and thiobarbituric acid-reactive substances caused by a choline-deficient, L-amino acid-defined diet in rats. Carcinogenesis 15: 1279–1283PubMedCrossRefGoogle Scholar
  85. 85.
    Abanobi SE, Lombardi B, Shinozuka H (1982) Stimulation of DNA synthesis and cell proliferation in the liver of rats fed a choline-devoid diet and their suppression by phenobarbital. Cancer Res 42: 412–415PubMedGoogle Scholar
  86. 86.
    Wainfan E, Poirier LA (1992) Methyl groups in carcinogenesis: Effects on DNA methylation and gene expression. Cancer Res 52: 2071s–2077sPubMedGoogle Scholar
  87. 87.
    Mikol Y, Hoover KL, Creasia D, Poirier LA (1983) Hepatocarcinogenesis in rats fed methyl-deficient, amino acid-defined diets. Carcinogenesis 4: 1619–1629PubMedCrossRefGoogle Scholar
  88. 88.
    Ghoshal AK, Farber E (1984) The induction of liver cancer by dietary deficiency of choline and methionine without added carcinogens. Carcinogenesis 5: 1367–1370PubMedCrossRefGoogle Scholar
  89. 89.
    Newberne PM, de Camargo JLV, Clark AJ (1982) Choline deficiency, partial hepatectomy, and liver tumors in rats and mice. Toxicol Pathol 10: 95–106Google Scholar
  90. 90.
    Counts JL, Sarmiento JI, Harbison ML, Downing JC, McClain RM, Goodman JI (1996) Cell proliferation and global methylation status changes in mouse liver after phenobarbital and/or cholinedevoid, methionine-deficient diet administration. Carcinogenesis 17: 1251–1257PubMedCrossRefGoogle Scholar
  91. 91.
    Counts JL, McClain RM, Goodman JI (1997) Comparison of effect of tumor promoter treatments on DNA methylation status and gene expression in B6C3F1 and C57BL/6 mouse liver and in B6C3F1 mouse liver tumors. Mol Carcinog 18: 97–106PubMedCrossRefGoogle Scholar
  92. 92.
    Bachman AN, Kamendulis LM, Goodman JI (2006) Diethanolamine and phenobarbital produce an altered pattern of methylation in GC-Rich regions of DNA in B6C3F1 mouse hepatocytes similar to that resulting from choline deficiency. Toxicol Sci 90: 317–325PubMedCrossRefGoogle Scholar
  93. 93.
    Watson RE, Goodman JI (2002) Effects of phenobarbital on DNA methylation in GC-rich regions of hepatic DNA from mice that exhibit different levels of susceptibility to liver tumorigenesis. Toxicol Sci 68: 51–58PubMedCrossRefGoogle Scholar
  94. 94.
    Bachman AN, Phillips JM, Goodman JI (2006) Phenobarbital induces progressive patterns of GC-rich and gene-specific altered DNA methylation in the liver of tumor-prone B6C3F1 mice. Toxicol Sci 91: 393–405PubMedCrossRefGoogle Scholar
  95. 95.
    Yamamoto Y, Moore R, Goldsworthy TL, Negishi M, Maronpot RR (2004) The orphan nuclear receptor constitutive active/androstane receptor is essential for liver tumor promotion by phenobarbital in mice. Cancer Res 64: 7197–7200PubMedCrossRefGoogle Scholar
  96. 96.
    Huang W, Zhang J, Washington M, Liu J, Parant JM, Lozano G, Moore DD (2005) Xenobiotic stress induces hepatomegaly and liver tumors via the nuclear receptor constitutive androstane receptor. Mol Endocrinol 19: 1646–1653PubMedCrossRefGoogle Scholar
  97. 97.
    Phillips JM, Goodman JI (2008) Identification of genes that may play critical roles in phenobarbital (PB)-induced liver tumorigenesis due to altered DNA methylation. Toxicol Sci 104: 86–99PubMedCrossRefGoogle Scholar
  98. 98.
    Kostka G, Urbanek K, Ludwicki JK (2007) The effect of phenobarbital on the methylation level of the p16 promoter region in rat liver. Toxicology 239: 127–135PubMedCrossRefGoogle Scholar
  99. 99.
    Wong IH, Zhang J, Lai PB, Lau WY, Lo YM (2003) Quantitative analysis of tumor-derived methylated p16INK4a sequences in plasma, serum, and blood cells of hepatocellular carcinoma patients. Clin Cancer Res 9: 1047–1052PubMedGoogle Scholar
  100. 100.
    Tryndyak VP, Muskhelishvili L, Kovalchuk O, Rodriguez-Juarez R, Montgomery B, Churchwell MI, Ross SA, Beland FA, Pogribny IP (2006) Effect of long-term tamoxifen exposure on genotoxic and epigenetic changes in rat liver: Implications for tamoxifen-induced hepatocarcinogenesis. Carcinogenesis 27: 1713–1720PubMedCrossRefGoogle Scholar
  101. 101.
    Kovalchuk O, Tryndyak VP, Montgomery B, Boyko A, Kutanzi K, Zemp F, Warbritton AR, Latendresse JR, Kovalchuk I, Beland FA, Pogribny IP (2007) Estrogen-induced rat breast carcinogenesis is characterized by alterations in DNA methylation, histone modifications, and aberrant microRNA expression. Cell Cycle 6: 2010–2018PubMedGoogle Scholar
  102. 102.
    Bachman AN, Curtin GM, Doolittle DJ, Goodman JI (2006) Altered methylation in gene-specific and GC-rich regions of DNA is progressive and nonrandom during promotion of skin tumorigenesis. Toxicol Sci 91: 406–418PubMedCrossRefGoogle Scholar
  103. 103.
    Sciarra A, Di Silverio F, Salciccia S, Autran Gomez AM, Gentilucci A, Gentile V (2007) Inflammation and chronic prostatic diseases: Evidence for a link? Eur Urol 52: 964–972PubMedCrossRefGoogle Scholar
  104. 104.
    Nelson WG, Yegnasubramanian S, Agoston AT, Bastian P.J., Lee BH, Nakayama M, De Marzo AM (2008) Abnormal DNA methylation, epigenetics, and prostate cancer. Front Biosci 12: 4254–4266CrossRefGoogle Scholar
  105. 105.
    Xie J, Itzkowitz SH (2008) Cancer in inflammatory bowel disease. World J Gastroenterol 14: 378–389PubMedCrossRefGoogle Scholar
  106. 106.
    Chan AOO, Rashid A (2006) CpG island methylation in precursors of gastrointestinal malignancies. Curr Mol Med 6: 401–408PubMedCrossRefGoogle Scholar
  107. 107.
    Maeda O, Ando T, Watanabe O, Ishiguro K, Ohmiya N, Niwa Y, Goto H (2006) DNA hypermethylation in colorectal neoplasms and inflammatory bowel disease: A mini review. Inflamm Pharmacol 14: 204–206CrossRefGoogle Scholar
  108. 108.
    Campos AC, Molognoni F, Melo FH, Galdieri LC, Carneiro CR, D’Almeida V, Correa M, Jasiulionis MG (2007) Oxidative stress modulates DNA methylation during melanocyte anchorage blockade associated with malignant transformation. Neoplasia 9: 1111–1121PubMedCrossRefGoogle Scholar
  109. 109.
    Jiang Y, Sun T, Xiong J, Cao J, Li G, Wang S (2007) Hyperhomocysteinemia-mediated DNA hypomethylation and its potential epigenetic role in rats. Acta Biochim Biophys Sin 39: 657–667PubMedCrossRefGoogle Scholar
  110. 110.
    Valinluck V, Sowers LC (2007) Inflammation-mediated cytosine damage: A mechanistic link between inflammation and the epigenetic alterations in human cancers. Cancer Res 67: 5583–5586PubMedCrossRefGoogle Scholar
  111. 111.
    De Santa F, Totaro MG, Prosperini E, Notarbartolo S, Testa G, Natoli G (2007) The histone H3 lysine-27 demethylase Jmjd3 links inflammation to inhibition of polycomb-mediated gene silencing. Cell 130: 1083–1094PubMedCrossRefGoogle Scholar
  112. 112.
    Szabo G, Mandrekar P, Dolganiuc A (2007) Innate immune response and hepatic inflammation. Semin Liver Dis 339-350Google Scholar
  113. 113.
    Kovalenko VM, Bagnyukova TV, Sergienko OV, Bondarenko LB, Shayakhmetova GM, Matvienko AV, Pogribny IP (2007) Epigenetic changes in the rat livers induced by pyrazinamide treatment. Toxicol Appl Pharmacol 225: 293–299PubMedCrossRefGoogle Scholar
  114. 114.
    Hastwell PW, Chai LL, Roberts KJ, Webster TW, Harvey JS, Rees RW, Walmsley RM (2006) High-specificity and high-sensitivity genotoxicity assessment in a human cell line: Validation of the GreenScreen HC GADD45a-GFP genotoxicity assay. Mutat Res 607: 160–175PubMedGoogle Scholar
  115. 115.
    Barreto G, Schäfer A, Marhold J, Stach D, Swaminathan SK, Handa V, Döderlein G, Maltry N, Wu W, Lyko F, Niehrs C (2007) Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 445: 671–675PubMedCrossRefGoogle Scholar
  116. 116.
    Preston RJ (2007) Epigenetic processes and cancer risk assessment. Mutat Res 616: 7–10PubMedGoogle Scholar
  117. 117.
    Rangarajan A, Weinberg RA (2003) Comparative biology of mouse versus human cells: Modeling human cancer in mice. Nat Rev Cancer 3: 952–959PubMedCrossRefGoogle Scholar
  118. 118.
    Vu TH, Jirtle RL, Hoffman AR (2007) Cross-species clues of an epigenetic imprinting regulatory code for the IGF2R gene. Cytogenet Genome Res 113: 202–208CrossRefGoogle Scholar
  119. 119.
    Goodman JI, Watson RE (2002) Altered DNA methylation: A secondary mechanism involved in carcinogenesis. Annu Rev Pharmacol Toxicol 42: 501–525PubMedCrossRefGoogle Scholar
  120. 120.
    Knight A, Bailey J, Balcombe J (2006) Animal carcinogenicity studies: 1. Poor human predictivity. Altern Lab Anim 34: 19–27PubMedGoogle Scholar
  121. 121.
    Knight A, Bailey J, Balcombe J (2006) Animal carcinogenicity studies: 2. Obstacles to extrapolation of data to humans. Altern Lab Anim 34: 29–38PubMedGoogle Scholar
  122. 122.
    Fielden MR, Brennan R, Gollub J (2007) A gene expression biomarker provides early prediction and mechanistic assessment of hepatic tumor induction by nongenotoxic chemicals. Toxicol Sci 99: 90–100PubMedCrossRefGoogle Scholar
  123. 123.
    Predictive Safety Testing Consortium CWG, Fielden MR, Nie A, McMillian M, Elangbam CS, Trela BA,Yang Y, Dunn RT II, Dragan Y, Fransson-Stehen R et al (2008) Inter-laboratory evaluation of genomic signatures for predicting carcinogenicity in the rat. Toxicol Sci 103: 28–34PubMedCrossRefGoogle Scholar
  124. 124.
    Paterlini-Brechot P, Benali NL (2007) Circulating tumor cells (CTC) detection: Clinical impact and future directions. Cancer Lett 253: 180–204PubMedCrossRefGoogle Scholar
  125. 125.
    Jacob K, Sollier C, Jabado N (2007) Circulating tumor cells: Detection, molecular profiling and future prospects. Expert Rev Proteomics 4: 741–756PubMedCrossRefGoogle Scholar
  126. 126.
    Herman JG (2004) Circulating methylated DNA. Ann NY Acad Sci 1022: 33–39PubMedCrossRefGoogle Scholar
  127. 127.
    Pantel K, Alix-Panabières C (2007) The clinical significance of circulating tumor cells. Nat Clin Pract Oncol 4: 62–63PubMedCrossRefGoogle Scholar
  128. 128.
    Nakagawa T, Martinez SR, Goto Y, Koyanagi K, Kitago M, Shingai T, Elashoff DA,Ye X, Singer FR, Giuliano AE, Hoon DSB (2007) Detection of circulating tumor cells in early-stage breast cancer metastasis to axillary lymph nodes. Clin Cancer Res 13: 4105–4110PubMedCrossRefGoogle Scholar
  129. 129.
    He W, Wang H, Hartmann LC, Cheng JX, Low PS (2007) In vivo quantitation of rare circulating tumor cells by multiphoton intravital flow cytometry. Proc Natl Acad Sci USA 104: 11760–11765PubMedCrossRefGoogle Scholar
  130. 130.
    Brena R, Huang T, Plass C (2006) Quantitative assessment of DNA methylation: Potential applications for disease diagnosis, classification, and prognosis in clinical settings. J Mol Med 84: 365–377PubMedCrossRefGoogle Scholar
  131. 131.
    Vogiatzi P, Aimola P, Scarano MI, Claudio PP (2007) Epigenome-derived drugs: Recent advances and future perspectives. Drug News Perspect 20: 627–633PubMedCrossRefGoogle Scholar
  132. 132.
    Ballestar E, Esteller M (2008) Epigenetic gene regulation in cancer. Adv Genet 61: 247–267PubMedCrossRefGoogle Scholar
  133. 133.
    Tsankova N, Renthal W, Kumar A, Nestler EJ (2007) Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8: 355–367PubMedCrossRefGoogle Scholar
  134. 134.
    Mazari L, Ouarzane M, Zouali M (2007) Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus. Proc Natl Acad Sci USA 104: 6317–6322PubMedCrossRefGoogle Scholar
  135. 135.
    Stöger R (2008) The thrifty epigenotype: An acquired and heritable predisposition for obesity and diabetes? Bioessays 30: 156–166PubMedCrossRefGoogle Scholar
  136. 136.
    Northrop JK, Thomas RM, Wells AD, Shen H (2006) Epigenetic remodeling of the IL-2 and IFN-g loci in memory CD8 T cells is influenced by CD4 T cells. J Immunol 177: 1062–1069PubMedGoogle Scholar
  137. 137.
    Foster SL, Hargreaves DC, Medzhitov R (2007) Gene-specific control of inflammation by TLRinduced chromatin modifications. Nature 447: 972–978PubMedGoogle Scholar
  138. 138.
    Arbibe L, Sansonetti PJ (2007) Epigenetic regulation of host response to LPS: Causing tolerance Mapping the epigenome-impact for toxicology 287 while avoiding toll errancy. Cell Host Microbe 1: 244–246PubMedCrossRefGoogle Scholar
  139. 139.
    Berthiaume J, Wallace K (2007) Persistent alterations to the gene expression profile of the heart subsequent to chronic doxorubicin treatment. Cardiovasc Toxicol 7: 178–191PubMedCrossRefGoogle Scholar
  140. 140.
    Wallace KB (2003) Doxorubicin-induced cardiac mitochondrionopathy. Pharmacol Toxicol 93: 105–115PubMedCrossRefGoogle Scholar
  141. 141.
    Shen L, Kondo Y, Ahmed S, Boumber Y, Konishi K, Guo Y, Chen X, Vilaythong JN, Issa JP (2007) Drug sensitivity prediction by CpG island methylation profile in the NCI-60 cancer cell line panel. Cancer Res 67: 11335–11343PubMedCrossRefGoogle Scholar
  142. 142.
    Gluckman PD, Hanson MA, Pinal C (2005) The developmental origins of adult disease. Matern Child Nutr 1: 130–141PubMedCrossRefGoogle Scholar
  143. 143.
    Gallou-Kabani C, Vigé, Alexandre, Gross MS, Junien C (2007) Nutri-epigenomics: Lifelong remodeling of our epigenomes by nutritional and metabolic factors and beyond. Clin Chem Lab Med 45: 321–327PubMedCrossRefGoogle Scholar
  144. 144.
    Cui H (2007) Loss of imprinting of IGF2 as an epigenetic marker for the risk of human cancer. Dis Markers 23: 105–112PubMedGoogle Scholar
  145. 145.
    Beck SL (2000) Does genomic imprinting contribute to valproic acid teratogenicity? Reprod Toxicol 15: 43–48CrossRefGoogle Scholar
  146. 146.
    Goebel G, Zitt M, Zitt M, Müller HM (2005) Circulating nucleic acids in plasma or serum (CNAPS) as prognostic and predictive markers in patients with solid neoplasias. Dis Markers 21: 105–120PubMedGoogle Scholar
  147. 147.
    Laird PW (2003) The power and the promise of DNA methylation markers. Nat Rev Cancer 3: 253–266PubMedCrossRefGoogle Scholar
  148. 148.
    Svedruzic ZM (2008) Mammalian cytosine DNA methyltransferase Dnmt1: Enzymatic mechanism, novel mechanism-based inhibitors, and RNA-directed DNA methylation. Curr Med Chem 15: 92–106PubMedCrossRefGoogle Scholar
  149. 149.
    Jeltsch A, Nellen W, Lyko F (2006) Two substrates are better than one: Dual specificities for Dnmt2 methyltransferases. Trends Biochem Sci 31: 306–308PubMedCrossRefGoogle Scholar
  150. 150.
    Chen T, Li E (2006) Establishment and maintenance of DNA methylation patterns in mammals. Curr Top Microbiol Immunol 301: 179–201PubMedCrossRefGoogle Scholar
  151. 151.
    LaSalle JM (2007) The odyssey of MeCP2 and parental imprinting. Epigenetics 2: 5–10Google Scholar
  152. 152.
    Nakao M, Matsui Si, Yamamoto S, Okumura K, Shirakawa M, Fujita N (2001) Regulation of transcription and chromatin by methyl-CpG binding protein MBD1 Brain Dev 23: S174-S176Google Scholar
  153. 153.
    Berger J, Bird A (2005) Role of MBD2 in gene regulation and tumorigenesis. Biochem Soc Trans 33: 1537–1540PubMedCrossRefGoogle Scholar
  154. 154.
    Kaji K, Nichols J, Hendrich B (2007) Mbd3, a component of the NuRD co-repressor complex, is required for development of pluripotent cells. Development 134: 1123–1132PubMedCrossRefGoogle Scholar
  155. 155.
    Abdel-Rahman WM, Knuutila S, Peltomaki P, Harrison DJ, Bader SA (2008) Truncation of MBD4 predisposes to reciprocal chromosomal translocations and alters the response to therapeutic agents in colon cancer cells. DNA Repair 7: 321–328PubMedCrossRefGoogle Scholar
  156. 156.
    Bedford MT (2007) Arginine methylation at a glance. J Cell Sci 120: 4243–4246PubMedCrossRefGoogle Scholar
  157. 157.
    Qian C, Zhou M (2006) SET domain protein lysine methyltransferases: Structure, specificity and catalysis. Cell Mol Life Sci 63: 2755–2763PubMedCrossRefGoogle Scholar
  158. 158.
    Zhang K, Dent SYR (2005) Histone modifying enzymes and cancer: Going beyond histones. J Cell Biochem 96: 1137–1148PubMedCrossRefGoogle Scholar
  159. 159.
    Feng Q, Wang H, Ng HH, Erdjument-Bromage H, Tempst P, Struhl K, Zhang Y (2002) Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr Biol 12: 1052–1058PubMedCrossRefGoogle Scholar
  160. 160.
    Swigut T, Wysocka J (2007) H3K27 demethylases, at long last. Cell 131: 29–32PubMedCrossRefGoogle Scholar
  161. 161.
    Benevolenskaya EV (2007) Histone H3K4 demethylases are essential in development and differentiation. Biochem Cell Biol 85: 435–443PubMedCrossRefGoogle Scholar
  162. 162.
    Culhane JC, Cole PA (2007) LSD1 and the chemistry of histone demethylation. Curr Opin Chem Biol 11: 561–568PubMedCrossRefGoogle Scholar
  163. 163.
    Kouzarides T (2007) Chromatin modifications and their function. Cell 128: 693–705PubMedCrossRefGoogle Scholar
  164. 164.
    Avvakumov N, Cote J (2007) The MYST family of histone acetyltransferases and their intimate links to cancer. Oncogene 26: 5395–5407PubMedCrossRefGoogle Scholar
  165. 165.
    Bhaumik SR, Smith E, Shilatifard A (2007) Covalent modifications of histones during development and disease pathogenesis. Nat Struct Mol Biol 14: 1008–1016PubMedCrossRefGoogle Scholar
  166. 166.
    Shukla V, Vaissiere T, Herceg Z (2008) Histone acetylation and chromatin signature in stem cell. Mutat Res 637: 1–15PubMedGoogle Scholar
  167. 167.
    Glozak MA, Seto E (2007) Histone deacetylases and cancer. Oncogene 26: 5420–5432PubMedCrossRefGoogle Scholar
  168. 168.
    Smith CL (2008) A shifting paradigm: Histone deacetylases and transcriptional activation. Bioessays 30: 15–24PubMedCrossRefGoogle Scholar
  169. 169.
    Nowak SJ, Corces VG (2004) Phosphorylation of histone H3: A balancing act between chromosome condensation and transcriptional activation Trends Genet 20: 214–220PubMedCrossRefGoogle Scholar
  170. 170.
    Shilatifard A (2006) Chromatin modifications by methylation and ubiquitination: Implications in the regulation of gene expression. Annu Rev Biochem 75: 243–269PubMedCrossRefGoogle Scholar
  171. 171.
    Iñiguez-Lluhí JA (2006) For a healthy histone code, a little SUMO in the tail keeps the acetyl away. ACS Chem Biol 1: 204–206PubMedCrossRefGoogle Scholar
  172. 172.
    Nathan D, Ingvarsdottir K, Sterner DE, Bylebyl GR, Dokmanovic M, Dorsey JA, Whelan KA, Krsmanovic M, Lane WS, Meluh PB et al (2006) Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications. Genes Dev 20: 966–976PubMedCrossRefGoogle Scholar
  173. 173.
    Gonzälez-Romero R, Méndez J, Ausió J, Eirín-López JM (2008) Quickly evolving histones, nucleosome stability and chromatin folding: All about histone H2A.Bbd. Gene 413: 1–7PubMedCrossRefGoogle Scholar
  174. 174.
    Zlatanova J, Thakar A (2008) H2A.Z: View from the Top. Structure 16: 166–179PubMedCrossRefGoogle Scholar
  175. 175.
    Loyola A, Almouzni G (2007) Marking histone H3 variants: How, when and why? Trends Biochem Sci 32: 425–433PubMedCrossRefGoogle Scholar
  176. 176.
    Bustin M, Catez F, Lim JH (2005) The dynamics of histone H1 function in chromatin. Mol Cell 17: 617–620PubMedCrossRefGoogle Scholar
  177. 177.
    Hudder A, Novak RF (2008) miRNAs: Effectors of environmental influences on gene expression and disease. Toxicol Sci 103: 228–240PubMedCrossRefGoogle Scholar
  178. 178.
    Taylor EL, Gant TW (2008) Emerging fundamental roles for non-coding RNA species in toxicology. Toxicology 246: 34–39PubMedCrossRefGoogle Scholar
  179. 179.
    Dali-Youcef N, Lagouge M, Froelich S, Koehl C, Schoonjans K, Auwerx J (2007) Sirtuins: The ‘magnificent seven’, function, metabolism and longevity. Ann Med 39: 335–345PubMedCrossRefGoogle Scholar
  180. 180.
    Rajasekhar VK, Begemann M (2007) Concise review: Roles of polycomb group proteins in development and disease: A stem cell perspective. Stem Cells 25: 2498–2510PubMedCrossRefGoogle Scholar
  181. 181.
    Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G (2007) Genome regulation by polycomb and trithorax proteins. Cell 128: 735–745PubMedCrossRefGoogle Scholar
  182. 182.
    Weber M, Schübeler D (2007) Genomic patterns of DNA methylation: Targets and function of an epigenetic mark. Curr Opin Cell Biol 19: 273–280PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag/Switzerland 2009

Authors and Affiliations

  • Jennifer Marlowe
    • 1
  • Soon-Siong Teo
    • 1
  • Salah-Dine Chibout
    • 1
  • François Pognan
    • 1
  • Jonathan Moggs
    • 1
  1. 1.Novartis Pharma AGInvestigative Toxicology, Preclinical SafetyBaselSwitzerland

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