NATUREIVol 447 24 May 2007 INSIGHT REVIEW 1. Van Speybroeck, L From epigenesis to epigenetics: the case of C H Waddington. Ann. Ny 42. Terranova, R, Agherbi, H, Boned, A, Meresse, S& Djabali, M Histone and DNA Acid. Sc.98161-81(2002 efects at ox genes in mice expressing saT domain-truncated formc 3. Niemitz, E L et al. Microdeletion of LIT1 in familial Beckwith-Wiedemann syndrome. Am J. 44. Rozenblatt-Rosen, O et al. The C-terminal SET ALL-l and TRITHORAX interact IGF2 imprinting 45. Versteege, let al. Truncating mutations ofhSNFS/INn in aggressive paediatric cancer. 604-611(2002) 6. Diaz-Meyer, N, Yang, Y, Sait, S N, Maher, E.R. Higgins, M. I. Altermative mechanisms 47. Scott, MR, Westphal, K H. Rigby, P W. Activation of mouse genes in transformed cells. th silencing of CDKNiC in Beckwith-Wiedemann syndrome. JMed Genet. ce14.557-56701983 hMLHI by epigenetic gene silencing a novel 7. Horsthemke, B. Buiting, K Imprinting defects on human chromosome 15. Cytogenet. rs. Proc Natl Acad. Sci. USA 95, 8698-8702(1998). Genome Res 113, 292-299(2006) by mutations in X-linked MECP2, encoding 50. DeBaun, M.R.& A Risk of cancer during the first four years of life in children at132398-400(1998) 10. Bienvenu, T& Chelly, I Molecular genetics of Rett syndrome: when DNA methylation 51. Cui, H, Horon, L L, Ohlsson, R, Hamilton, S.R. Feinberg, A P Loss of imprinting in Il. u G recognized Nature Rev. Genet 7, 415-426(2006) normal tissue of colorectal cancer patients with microsatellite instability Nature Med. 4, rase gene Nature 402, 187-191(1999) 52. Cui, H et al. Loss of IGF2 imprinting a potential marker of colorectal ca sk. Science ection and terminal erentiation in the ICF syndrome. Blood 103, 2683-2690(2004 53. Woodson, K et al Loss of insulin-like growth factor ll imprinting and the presence of 13. Gibbons, R.J.& Higgs, D R. Molecular-clinical spectrum of the ATR-x syndrome. Am. I screen-detected colorectal adenomas in women. Natl Cancer Inst. 96, 407-410 Med Genet97204-21202000) 14. Petri, Fet al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co- 54. Toyota, M. et al CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sai. 15. Feinberg, A P. Vogelstein, B Hypomethylation distinguishes genes of some human 55. parts. Nature 301, 89-92(1983) 16. Wilson, AS, Power, B.E. Molloy, P L DNa hypomethylation and human diseases. 56. Yamada, Y et al. Opposing effects of DNA hypor tion on intestinal and liver achim. Biophys. Acta 1775, 138-162(2007 carcinogenesis. Proc Natl Acad Sci. USA 102, 13580-13585(2005). cko, B. The history of cancer epigenetics. Nature Rev. Cancer 4, 143-153 57. Gaudet Induction of tumors in mice by genomic hypomethylation. Science 300 18. Brueckner, B et al The human let-7a-3 locus contains an epigenetically regulated R Chromosomal instability and tumors fu, Het al. Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated 59. Laird, P Wet al. Suppression of inte 20. Greger, V, Passarge, E, Hopping, w, Messmer, E& Horsthemke, B Epigenetic changes 60. Chen, W.Yet al. Heterozygous disruption of Hicl predisposes mice to a gender-dependent ay contribute to the formation and spontaneous regression of retinoblastoma. Human Gent33197-202(2003) 61. Sakatani, T etal Loss of imprinting of igf2 alters intestinal maturation and tumorigenesis in 21. Jones, P. A Baylin, S.B. The fundamental role of epigenetic events in cancer. Nature Rev. mice. Science307,1976-1978(2005) Genet.3,415-428(2002) et. 24, 132-138 (200on has non-random and tumour-type-. 的A082535(D时bm 62. Holm. T.M. et aL Global loss 23. Esteller, M, Corn, P.G., Baylin, S.B.& Herman, J.G. A gene hypermethylation profile of 721-33(2006 human cancer. Cancer Res 61, 3225-3229(200 64. Harper, Iet al. Soluble IGF2 receptor rescues Apc r" intestinal adenoma progression tire chromosome band. Nature Genet. 38, 540-549(2006) 65. Ravenel, J.D. etol Loss of imprinting of insulin-like growth factor-l(IGF2) gene in ansferases for CpG islands in mouse distinguishing specific biologic subtypes of Wilms tumor. I Natl Cancer Inst. 93, 1698-1703 66. Hochedlinger, K et al Reprogramming of a melanoma genome by nuclear transplantation. differential DNA methylation in normal and transformed human cells. Nature Genet. 37, enes Dev 75-1885(2004) 67. Hu, M. et al Distinct epigenetic changes in the stromal cells of breast cancers. Nature 27. Gius, Det al. Distinct effects on gene expression of chemical and genetic manipulation of the cancer epigenome revealed by a multimodality approach. Cancer Cell 6, 361-371 embryonic stem cells. Cell 125, 315-326(200cture marks key developmental genes in 28. Scrable, H et al A model for embryonalrhabdomyosarcoma tumorigenesis that inmolves 69. Horton, S.J.et al. Continuous MLL-ENL expression is necessary to establish a Hox Code genome imprinting. Proc Natl Acad Sci. USA 86, 7480-7484( 1989). and maintain immortalization of hematopoietic progenitor cells. Cancer Res 65, 29. Rainier, Set al. Relaxation of imprinted genes in human cancer. Nature 362, 747-749 70. Krivtsov, A V et al. Transformation from committed progenitor to leukaemia stem cell insulin-like growth factor l gene imprinting implicated in e442,818-822(2006) Wilms'tumour Nature 362, 749-751(1993) 7. Boyer, L A et al. Polyco repress developmental regulators in murine kinberg. A P Gend ature Genet. 4, 110-113 mbryonic stem cells. Nature 441, 349. 72. Skuse, D H et ol Evidence from Turner s syndrome of an imprinted X-linked locus affecting 32. Kondo, M. et al. Frequent loss of imprinting of the H19 gene is often associated with its nitive function. Nature 387, 705-708 (1997) lung cancers. Oncogene 10, 1193-1198(1995 tion of a cluster of X-linked imprinted genes in mice 33. inting of GF2 and not H19 in breast cancer, adjacent ature Genet37620-624(2005) 34. Murphy, S.K. et al Frequent IGF2/H19 domain epigenetic alterations and elevated Gf2 chol. Med.25,63-7701995) 75. Kates, W.R. et aL Neuroanatomic variation in monozygotic twin pairs discordant for the 35. Uyeno, Set al. IGF2 but not H19 shows loss of imprinting in human glioma. Cancer Res y161539-546(2004) 5356-535901996) tomi,G. Okazaki, Y Genetic or epigenet cing of ARHI, an imprinted tumor suppressor using discordance between monozygotic twins as a clue to molecular basis of ne in which the function is 37. Astuti, D et al. Epigenetic alteration at the dlK1-GTL2 imprinted domain in human 77. International Me Autism Consortium Consortium. Further aplasia: analysis of neuroblastoma, phaeochromocytoma and wilms tumour. Br. 1. the autism susceptibility locus AU/TSI on chromosome 7q. Hum. MoL VMEST in invasive breast cancer. 78. Mcinnis, M. Get al. Genome-wide scan of bipolar disorder in 65 pedigrees: 39. Varambally, S, et al The polycomb group protein EZH2 is involved in progression of 79. Lu, Qet al. Epigenetics, disease, and therapeutic interventions. Ageing Res Rev. 5,449-467 at Lys 20of histone H4 Nature gene37,391-400(2005) DNA 41. Tamaru, H. Selker, E U. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa Nature 414, 277-283(2001) mike dysteraesi ic ic. Zin tibet 92.38-530(93,5 suffcient to cause lupus. 9 @2007 Nature Publishing Group1. Van Speybroeck, L. From epigenesis to epigenetics: the case of C. H. Waddington. Ann. NY Acad. Sci. 981, 61–81 (2002). 2. Debaun, M. R. & Feinberg, A. P. in Inborn Errors of Development: The Molecular Basis of Clinical Disorders of Morphogenesis (ed. Epstein, C. J.) 758–765 (Oxford Univ. Press, Oxford, USA, 2004). 3. Niemitz, E. L. et al. Microdeletion of LIT1 in familial Beckwith–Wiedemann syndrome. Am. J. Hum. Genet. 75, 844–849 (2004). 4. Sparago, A. et al. Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith–Wiedemann syndrome. Nature Genet. 36, 958–960 (2004). 5. DeBaun, M. R. et al. Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith–Wiedemann syndrome with cancer and birth defects. Am. J. Hum. Genet. 70, 604–611 (2002). 6. Diaz-Meyer, N., Yang, Y., Sait, S. N., Maher, E. R. & Higgins, M. J. Alternative mechanisms associated with silencing of CDKN1C in Beckwith–Wiedemann syndrome. J. Med. Genet. 42, 648–655 (2005). 7. Horsthemke, B. & Buiting, K. Imprinting defects on human chromosome 15. Cytogenet. Genome Res.113, 292–299 (2006). 8. Lalande, M. Imprints of disease at GNAS1. J. Clin. Invest.107, 793–794 (2001). 9. Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet. 23, 185–188 (1999). 10. Bienvenu, T. & Chelly, J. Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized. Nature Rev. Genet. 7, 415–426 (2006). 11. Xu, G. L. et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402, 187–191 (1999). 12. Blanco-Betancourt, C. E. et al. Defective B-cell-negative selection and terminal differentiation in the ICF syndrome. Blood 103, 2683–2690 (2004). 13. Gibbons, R. J. & Higgs, D. R. Molecular-clinical spectrum of the ATR-X syndrome. Am. J. Med. Genet. 97, 204–212 (2000). 14. Petrif, F. et al. Rubinstein–Taybi syndrome caused by mutations in the transcriptional co￾activator CBP. Nature 376, 348–351 (2002). 15. Feinberg, A. P. & Vogelstein, B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89–92 (1983). 16. Wilson, A. S., Power, B. E. & Molloy, P. L. DNA hypomethylation and human diseases. Biochim. Biophys. Acta 1775, 138–162 (2007). 17. Feinberg, A. P. & Tycko, B. The history of cancer epigenetics. Nature Rev. Cancer 4, 143–153 (2004). 18. Brueckner, B. et al. The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Res. 67, 1419–1423 (2007). 19. Wu, H. et al. Hypomethylation-linked activation of PAX2 mediates tamoxifen-stimulated endometrial carcinogenesis. Nature 438, 981–987 (2005). 20. Greger, V., Passarge, E., Hopping, W., Messmer, E. & Horsthemke, B. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Human Genet. 83, 155–158 (1989). 21. Jones, P. A. & Baylin, S. B. The fundamental role of epigenetic events in cancer. Nature Rev. Genet. 3, 415–428 (2002). 22. Costello, J. F. et al. Aberrant CpG-island methylation has non-random and tumour-type￾specific patterns. Nature Genet. 24, 132–138 (2000). 23. Esteller, M., Corn, P. G., Baylin, S. B. & Herman, J. G. A gene hypermethylation profile of human cancer. Cancer Res. 61, 3225–3229 (2001). 24. Frigola, J. et al. Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band. Nature Genet. 38, 540–549 (2006). 25. Hattori, N. et al. Preference of DNA methyltransferases for CpG islands in mouse embryonic stem cells. Genome Res.14, 1733–1740 (2004). 26. Weber, M. et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nature Genet. 37, 853–862 (2005). 27. Gius, D. et al. Distinct effects on gene expression of chemical and genetic manipulation of the cancer epigenome revealed by a multimodality approach. Cancer Cell 6, 361–371 (2004). 28. Scrable, H. et al. A model for embryonal rhabdomyosarcoma tumorigenesis that involves genome imprinting. Proc. Natl Acad. Sci. USA 86, 7480–7484 (1989). 29. Rainier, S. et al. Relaxation of imprinted genes in human cancer. Nature 362, 747–749 (1993). 30. Ogawa, O. et al. Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms’ tumour. Nature 362, 749–751 (1993). 31. Feinberg, A. P. Genomic imprinting and gene activation in cancer. Nature Genet. 4, 110–113 (1993). 32. Kondo, M. et al. Frequent loss of imprinting of the H19 gene is often associated with its overexpression in human lung cancers. Oncogene 10, 1193–1198 (1995). 33. van Roozendaal, C. E. et al. Loss of imprinting of IGF2 and not H19 in breast cancer, adjacent normal tissue and derived fibroblast cultures. FEBS Lett. 437, 107–111 (1998). 34. Murphy, S. K. et al. Frequent IGF2/H19 domain epigenetic alterations and elevated IGF2 expression in epithelial ovarian cancer. Mol. Cancer Res. 4, 283–292 (2006). 35. Uyeno, S. et al. IGF2 but not H19 shows loss of imprinting in human glioma. Cancer Res. 56, 5356–5359 (1996). 36. Yuan, J. et al. Aberrant methylation and silencing of ARHI, an imprinted tumor suppressor gene in which the function is lost in breast cancers. Cancer Res 63, 4174–4180 (2003). 37. Astuti, D. et al. Epigenetic alteration at the DLK1–GTL2 imprinted domain in human neoplasia: analysis of neuroblastoma, phaeochromocytoma and Wilms’ tumour. Br. J. Cancer 92, 1574–1580 (2005). 38. Pedersen, I. S. et al. Frequent loss of imprinting of PEG1/MEST in invasive breast cancer. Cancer Res 59, 5449–5451 (1999). 39. Varambally, S., et al. The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature 419, 624–629 (2002). 40. Fraga, M. F. et al. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature Genet. 37, 391–400 (2005). 41. Tamaru, H. & Selker, E. U. A histone H3 methyltransferase controls DNA methylation in Neurospora crassa. Nature 414, 277–283 (2001). 42. Terranova, R., Agherbi, H., Boned, A., Meresse, S. & Djabali, M. Histone and DNA methylation defects at Hox genes in mice expressing a SET domain-truncated form of Mll. Proc. Natl Acad. Sci. USA 103, 6629–6634 (2006). 43. Esteve, P. O. et al. Direct interaction between DNMT1and G9a coordinates DNA and histone methylation during replication. Genes Dev. 20, 3089–3103 (2006). 44. Rozenblatt-Rosen, O. et al. The C-terminal SET domains of ALL-1 and TRITHORAX interact with the INI1 and SNR1 proteins, components of the SWI/SNF complex. Proc. Natl Acad. Sci. USA 95, 4152–4157 (1998). 45. Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998). 46. Kurotaki, N. et al. Haploinsufficiency of NSD1 causes Sotos syndrome. Nature Genet. 30, 365–366 (2002). 47. Scott, M. R., Westphal, K. H. & Rigby, P. W. Activation of mouse genes in transformed cells. Cell 34, 557–567 (1983). 48. Veigl, M. L. et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc. Natl Acad. Sci. USA 95, 8698–8702 (1998). 49. Bachman, K. E. et al. Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene. Cancer Cell 3, 89–95 (2003). 50. DeBaun, M. R. & Tucker, M. A. Risk of cancer during the first four years of life in children from the Beckwith–Wiedemann syndrome registry. J. Pediatr.132, 398–400 (1998). 51. Cui, H., Horon, I. L., Ohlsson, R., Hamilton, S. R. & Feinberg, A. P. Loss of imprinting in normal tissue of colorectal cancer patients with microsatellite instability. Nature Med. 4, 1276–1280 (1998). 52. Cui, H. et al. Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science 299, 1753–1755 (2003). 53. Woodson, K. et al. Loss of insulin-like growth factor-II imprinting and the presence of screen-detected colorectal adenomas in women. J. Natl Cancer Inst. 96, 407–410 (2004). 54. Toyota, M. et al. CpG island methylator phenotype in colorectal cancer. Proc. Natl Acad. Sci. USA 96, 8681–8686 (1999). 55. Holst, C. R. et al. Methylation of p16INK4a promoters occurs in vivo in histologically normal human mammary epithelia. Cancer Res. 63, 1596–1601 (2003). 56. Yamada, Y. et al. Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proc. Natl Acad. Sci. USA 102, 13580–13585 (2005). 57. Gaudet, F. et al. Induction of tumors in mice by genomic hypomethylation. Science 300, 489–492 (2003). 58. Eden, A., Gaudet, F., Waghmare, A. & Jaenisch, R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 300, 455 (2003). 59. Laird, P. W. et al. Suppression of intestinal neoplasia by DNA hypomethylation. Cell 81, 197–205 (1995). 60. Chen, W. Y. et al. Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nature Genet. 33, 197–202 (2003). 61. Sakatani, T. et al. Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice. Science 307, 1976–1978 (2005). 62. Holm, T. M. et al. Global loss of imprinting leads to widespread tumorigenesis in adult mice. Cancer Cell 8, 275–285 (2005). 63. Feinberg, A. P., Ohlsson, R. & Henikoff, S. The epigenetic progenitor origin of human cancer. Nature Rev. Genet. 7, 21–33 (2006). 64. Harper, J. et al. Soluble IGF2 receptor rescues ApcMin/+ intestinal adenoma progression induced by Igf2 loss of imprinting. Cancer Res. 66, 1940–1948 (2006). 65. Ravenel, J.D. et al. Loss of imprinting of insulin-like growth factor-II (IGF2) gene in distinguishing specific biologic subtypes of Wilms tumor. J. Natl Cancer Inst. 93, 1698–1703 (2001). 66. Hochedlinger, K. et al. Reprogramming of a melanoma genome by nuclear transplantation. Genes Dev.18, 1875–1885 (2004). 67. Hu, M. et al. Distinct epigenetic changes in the stromal cells of breast cancers. Nature Genet. 37, 899–905 (2005). 68. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell125, 315–326 (2006). 69. Horton, S. J. et al. Continuous MLL–ENL expression is necessary to establish a ‘Hox Code’ and maintain immortalization of hematopoietic progenitor cells. Cancer Res. 65, 9245–9252 (2005). 70. Krivtsov, A. V. et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442, 818–822 (2006). 71. Boyer, L. A. et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 441, 349–353 (2006). 72. Skuse, D. H. et al. Evidence from Turner’s syndrome of an imprinted X-linked locus affecting cognitive function. Nature 387, 705–708 (1997). 73. Raefski, A. S. & O’Neill, M. J. Identification of a cluster of X-linked imprinted genes in mice. Nature Genet. 37, 620–624 (2005). 74. Bailey, A. et al. Autism as a strongly genetic disorder: evidence from a British twin study. Psychol. Med. 25, 63–77 (1995). 75. Kates, W. R. et al. Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism. Am. J. Psychiatry 161, 539–546 (2004). 76. Kato, T., Iwamoto, K., Kakiuchi, C., Kuratomi, G. & Okazaki, Y. Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders. Mol. Psychiatry 10, 622–630 (2005). 77. International Molecular Genetic Study of Autism ConsortiumConsortium. Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. Hum. Mol. Genet.10, 973–982 (2001). 78. McInnis, M. G. et al. Genome-wide scan of bipolar disorder in 65 pedigrees: supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12. Mol. Psychiatry 8, 288–298 (2003). 79. Lu, Q. et al. Epigenetics, disease, and therapeutic interventions. Ageing Res. Rev. 5, 449–467 (2006). 80. Quddus, J. et al. Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus￾like disease in syngeneic mice. J. Clin. Invest. 92, 38–53 (1993). 439 NATURE|Vol 447|24 May 2007 INSIGHT REVIEW ￾