Molecular mechanisms of genomic imprinting and clinical implications for cancer

Santiago Uribe-Lewis; Kathryn Woodfine; Lovorka Stojic; Adele Murrell

doi:10.1017/S1462399410001717

Molecular mechanisms of genomic imprinting and clinical implications for cancer

Published online by Cambridge University Press: 25 January 2011

Santiago Uribe-Lewis ,

Kathryn Woodfine ,

Lovorka Stojic and

Adele Murrell

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Santiago Uribe-Lewis: Affiliation:
Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
Kathryn Woodfine: Affiliation:
Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
Lovorka Stojic: Affiliation:
Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
Adele Murrell*: Affiliation:
Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK.
*: *Corresponding author: Adele Murrell, Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK. E-mail: [email protected]

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Abstract

Genomic imprinting is an epigenetic marking of genes in the parental germline that ensures the stable transmission of monoallelic gene expression patterns in a parent-of-origin-specific manner. Epigenetic marking systems are thus able to regulate gene activity independently of the underlying DNA sequence. Several imprinted gene products regulate cell proliferation and fetal growth; loss of their imprinted state, which effectively alters their dosage, might promote or suppress tumourigenic processes. Conversely, global epigenetic changes that underlie tumourigenesis might affect imprinted gene expression. Here, we review imprinted genes with regard to their roles in epigenetic predisposition to cancer, and discuss acquired epigenetic changes (DNA methylation, histone modifications and chromatin conformation) either as a result of cancer or as an early event in neoplasia. We also address recent work showing the potential role of noncoding RNA in modifying chromatin and affecting imprinted gene expression, and summarise the effects of loss of imprinting in cancer with regard to the roles that imprinted genes play in regulating growth signalling cascades. Finally, we speculate on the clinical applications of epigenetic drugs in cancer.

Type: Review Article
Information: Expert Reviews in Molecular Medicine , Volume 13 , March 2011 , e2

DOI: https://doi.org/10.1017/S1462399410001717 [Opens in a new window]
Copyright: Copyright © Cambridge University Press 2011

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References

1Cremer, T. and Cremer, M. (2010) Chromosome territories. Cold Spring Harbor Perspectives in Biology 2, a003889CrossRef Google Scholar PubMed

2Schoenfelder, S., Clay, I. and Fraser, P. (2010) The transcriptional interactome: gene expression in 3D. Current Opinion in Genetics and Development 20, 127-133CrossRef Google Scholar PubMed

3Kouzarides, T. (2007) Chromatin modifications and their function. Cell 128, 693-705CrossRef Google Scholar PubMed

4Jones, P.A. and Baylin, S.B. (2007) The epigenomics of cancer. Cell 128, 683-692CrossRef Google Scholar PubMed

5Filion, G.J. et al. (2010) Systematic protein location mapping reveals five principal chromatin types in Drosophila cells. Cell 143, 212-224CrossRef Google Scholar PubMed

6Rinn, J.L. et al. (2007) Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311-1323CrossRef Google Scholar PubMed

7Varmuza, S. and Mann, M. (1994) Genomic imprinting – defusing the ovarian time bomb. Trends in Genetics 10, 118-123CrossRef Google Scholar PubMed

8Daponte, A. et al. (2008) Immature teratoma in pregnancy: a case report and literature review. European Journal of Gynaecological Oncology 29, 300-304Google Scholar PubMed

9Cheung, A.N. et al. (2009) Pathogenesis of choriocarcinoma: clinical, genetic and stem cell perspectives. Future Oncology 5, 217-231CrossRef Google Scholar PubMed

10Weksberg, R., Shuman, C. and Beckwith, J.B. (2010) Beckwith–Wiedemann syndrome. European Journal of Human Genetics 18, 8-14CrossRef Google Scholar PubMed

11Engel, J.R. et al. (2000) Epigenotype–phenotype correlations in Beckwith–Wiedemann syndrome. Journal of Medical Genetics 37, 921-926CrossRef Google Scholar PubMed

12Brown, K.W. et al. (2008) Frequency and timing of loss of imprinting at 11p13 and 11p15 in Wilms' tumor development. Molecular Cancer Research 6, 1114-1123CrossRef Google Scholar PubMed

13Murrell, A. (2006) Genomic imprinting and cancer: from primordial germ cells to somatic cells. ScientificWorldJournal 6, 1888-1910CrossRef Google Scholar PubMed

14Davies, H.D. et al. (2003) Myeloid leukemia in Prader–Willi syndrome. Jornal de Pediatria 142, 174-178CrossRef Google Scholar PubMed

15Kanber, D. et al. (2009) The human retinoblastoma gene is imprinted. PLoS Genetics 5, e1000790CrossRef Google Scholar PubMed

16Toguchida, J. et al. (1989) Preferential mutation of paternally derived RB gene as the initial event in sporadic osteosarcoma. Nature 338, 156-158CrossRef Google Scholar PubMed

17Kato, M.V. et al. (1994) Parental origin of germ-line and somatic mutations in the retinoblastoma gene. Human Genetics 94, 31-38CrossRef Google Scholar PubMed

18Schuler, A. et al. (2005) Age at diagnosis of isolated unilateral retinoblastoma does not distinguish patients with and without a constitutional RB1 gene mutation but is influenced by a parent-of-origin effect. European Journal of Cancer 41, 735-740CrossRef Google Scholar

19Kong, A. et al. (2009) Parental origin of sequence variants associated with complex diseases. Nature 462, 868-874CrossRef Google Scholar PubMed

20Murrell, A. et al. (2008) Distinct methylation changes at the IGF2-H19 locus in congenital growth disorders and cancer. PLoS One 3, e1849CrossRef Google Scholar

21Edwards, C.A. and Ferguson-Smith, A.C. (2007) Mechanisms regulating imprinted genes in clusters. Current Opinion in Cell Biology 19, 281-289CrossRef Google Scholar PubMed

22Feng, W. et al. (2008) Imprinted tumor suppressor genes ARHI and PEG3 are the most frequently down-regulated in human ovarian cancers by loss of heterozygosity and promoter methylation. Cancer 112, 1489-1502CrossRef Google Scholar PubMed

23Riemenschneider, M.J., Reifenberger, J. and Reifenberger, G. (2008) Frequent biallelic inactivation and transcriptional silencing of the DIRAS3 gene at 1p31 in oligodendroglial tumors with 1p loss. International Journal of Cancer 122, 2503-2510CrossRef Google Scholar PubMed

24Weber, F. et al. (2005) Silencing of the maternally imprinted tumor suppressor ARHI contributes to follicular thyroid carcinogenesis. Journal of Clinical Endocrinology and Metabolism 90, 1149-1155CrossRef Google Scholar PubMed

25Yuan, J. et al. (2003) Aberrant methylation and silencing of ARHI, an imprinted tumor suppressor gene in which the function is lost in breast cancers. Cancer Research 63, 4174-4180Google Scholar PubMed

26Kamikihara, T. et al. (2005) Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer. International Journal of Cancer 115, 690-700CrossRef Google Scholar PubMed

27Martinez, R. et al. (2009) A microarray-based DNA methylation study of glioblastoma multiforme. Epigenetics 4, 255-264CrossRef Google Scholar PubMed

28Li, Y., Meng, G. and Guo, Q.N. (2008) Changes in genomic imprinting and gene expression associated with transformation in a model of human osteosarcoma. Experimental and Molecular Pathology 84, 234-239CrossRef Google Scholar

29Ulaner, G.A. et al. (2003) Loss of imprinting of IGF2 and H19 in osteosarcoma is accompanied by reciprocal methylation changes of a CTCF-binding site. Human Molecular Genetics 12, 535-549CrossRef Google Scholar PubMed

30Cui, H. et al. (2002) Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Research 62, 6442-6446Google Scholar PubMed

31Byun, H.M. et al. (2007) Examination of IGF2 and H19 loss of imprinting in bladder cancer. Cancer Research 67, 10753-10758CrossRef Google Scholar PubMed

32Takai, D. et al. (2001) Large scale mapping of methylcytosines in CTCF-binding sites in the human H19 promoter and aberrant hypomethylation in human bladder cancer. Human Molecular Genetics 10, 2619-2626CrossRef Google Scholar PubMed

33Wu, J. et al. (2008) Hypomethylated and hypermethylated profiles of H19DMR are associated with the aberrant imprinting of IGF2 and H19 in human hepatocellular carcinoma. Genomics 91, 443-450CrossRef Google Scholar PubMed

34Furukawa, S. et al. (2009) Yolk sac tumor but not seminoma or teratoma is associated with abnormal epigenetic reprogramming pathway and shows frequent hypermethylation of various tumor suppressor genes. Cancer Science 100, 698-708CrossRef Google Scholar PubMed

35Kondo, M. et al. (1995) Frequent loss of imprinting of the H19 gene is often associated with its overexpression in human lung cancers. Oncogene 10, 1193-1198Google Scholar PubMed

36Douc-Rasy, S. et al. (1996) High incidence of loss of heterozygosity and abnormal imprinting of H19 and IGF2 genes in invasive cervical carcinomas. Uncoupling of H19 and IGF2 expression and biallelic hypomethylation of H19. Oncogene 12, 423-430Google Scholar PubMed

37Hashimoto, K. et al. (1997) Loss of H19 imprinting and up-regulation of H19 and SNRPN in a case with malignant mixed Mullerian tumor of the uterus. Human Pathology 28, 862-865CrossRef Google Scholar

38Lynch, C.A. et al. (2002) Reactivation of a silenced H19 gene in human rhabdomyosarcoma by demethylation of DNA but not by histone hyperacetylation. Molecular Cancer 1, 2CrossRef Google Scholar

39Sun, Y. et al. (2006) IGF2 is critical for tumorigenesis by synovial sarcoma oncoprotein SYT-SSX1. Oncogene 25, 1042-1052CrossRef Google Scholar PubMed

40Kawakami, T. et al. (2006) Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin. Oncogene 25, 3225-3236CrossRef Google Scholar PubMed

41Cui, H. et al. (2001) Loss of imprinting of insulin-like growth factor-II in Wilms' tumor commonly involves altered methylation but not mutations of CTCF or its binding site. Cancer Research 61, 4947-4950Google Scholar PubMed

42Yuan, E. et al. (2005) Genomic profiling maps loss of heterozygosity and defines the timing and stage dependence of epigenetic and genetic events in Wilms' tumors. Molecular Cancer Research 3, 493-502CrossRef Google Scholar PubMed

43Nakagawa, H. et al. (2001) Loss of imprinting of the insulin-like growth factor II gene occurs by biallelic methylation in a core region of H19-associated CTCF-binding sites in colorectal cancer. Proceedings of the National Academy of Sciences of the United States of America 98, 591-596CrossRef Google Scholar

44De Castro Valente Esteves, L.I. et al. (2006) H19-DMR allele-specific methylation analysis reveals epigenetic heterogeneity of CTCF binding site 6 but not of site 5 in head-and-neck carcinomas: a pilot case-control analysis. International Journal of Molecular Medicine 17, 397-404Google Scholar

45Honda, S. et al. (2008) Loss of imprinting of IGF2 correlates with hypermethylation of the H19 differentially methylated region in hepatoblastoma. British Journal of Cancer 99, 1891-1899CrossRef Google Scholar PubMed

46Li, X. et al. (1998) Promoter-specific methylation and expression alterations of igf2 and h19 are involved in human hepatoblastoma. International Journal of Cancer 75, 176-1803.0.CO;2-R>CrossRef Google Scholar PubMed

47Paradowska, A. et al. (2009) Aberrant epigenetic modifications in the CTCF binding domain of the IGF2/H19 gene in prostate cancer compared with benign prostate hyperplasia. International Journal of Oncology 35, 87-96CrossRef Google Scholar PubMed

48Arima, T. et al. (1997) Association of IGF2 and H19 imprinting with choriocarcinoma development. Cancer Genetics and Cytogenetics 93, 39-47CrossRef Google Scholar PubMed

49Dammann, R.H. et al. (2010) Frequent aberrant methylation of the imprinted IGF2/H19 locus and LINE1 hypomethylation in ovarian carcinoma. International Journal of Oncology 36, 171-179Google Scholar PubMed

50Cheng, Y.W. et al. (2010) Loss of imprinting and marked gene elevation are 2 forms of aberrant IGF2 expression in colorectal cancer. International Journal of Cancer 127, 568-577CrossRef Google Scholar PubMed

51Eriksson, T. et al. (2001) Methylation changes in the human IGF2 p3 promoter parallel IGF2 expression in the primary tumor, established cell line, and xenograft of a human hepatoblastoma. Experimental Cell Research 270, 88-95CrossRef Google Scholar PubMed

52Poirier, K. et al. (2003) Loss of parental-specific methylation at the IGF2 locus in human hepatocellular carcinoma. Journal of Pathology 201, 473-479CrossRef Google Scholar PubMed

53Sullivan, M.J. et al. (1999) Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation. Oncogene 18, 7527-7534CrossRef Google Scholar PubMed

54Ito, Y. et al. (2008) Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer. Human Molecular Genetics 17, 2633-2643CrossRef Google Scholar PubMed

55Baba, Y. et al. (2010) Hypomethylation of the IGF2 DMR in colorectal tumors, detected by bisulfite pyrosequencing, is associated with poor prognosis. Gastroenterology Aug 2; [Epub ahead of print]CrossRef Google Scholar PubMed

56Li, Y. et al. (2009) Hypomethylation of the P3 promoter is associated with up-regulation of IGF2 expression in human osteosarcoma. Human Pathology 40, 1441-1447CrossRef Google Scholar PubMed

57Issa, J.P. et al. (1996) Switch from monoallelic to biallelic human IGF2 promoter methylation during aging and carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America 93, 11757-11762CrossRef Google Scholar PubMed

58Xu, W. et al. (2006) LOI of IGF2 is associated with esophageal cancer and linked to methylation status of IGF2 DMR. Journal of Experiments and Clinical Cancer Research 25, 543-547Google Scholar PubMed

59El-Maarri, O. et al. (2003) Maternal alleles acquiring paternal methylation patterns in biparental complete hydatidiform moles. Human Molecular Genetics 12, 1405-1413CrossRef Google Scholar PubMed

60Dejeux, E. et al. (2009) Hypermethylation of the IGF2 differentially methylated region 2 is a specific event in insulinomas leading to loss-of-imprinting and overexpression. Endocrine-related Cancer 16, 939-952CrossRef Google Scholar PubMed

61Nakano, S. et al. (2006) Expression profile of LIT1/KCNQ1OT1 and epigenetic status at the KvDMR1 in colorectal cancers. Cancer Science 97, 1147-1154CrossRef Google Scholar PubMed

62Kuang, S.Q. et al. (2007) Differential tumor suppressor properties and transforming growth factor-beta responsiveness of p57KIP2 in leukemia cells with aberrant p57KIP2 promoter DNA methylation. Oncogene 26, 1439-1448CrossRef Google Scholar PubMed

63Pike, B.L. et al. (2008) DNA methylation profiles in diffuse large B-cell lymphoma and their relationship to gene expression status. Leukemia 22, 1035-1043CrossRef Google Scholar PubMed

64Astuti, D. et al. (2005) Epigenetic alteration at the DLK1-GTL2 imprinted domain in human neoplasia: analysis of neuroblastoma, phaeochromocytoma and Wilms' tumour. British Journal of Cancer 92, 1574-1580CrossRef Google Scholar PubMed

65Kawakami, T. et al. (2006) Imprinted DLK1 is a putative tumor suppressor gene and inactivated by epimutation at the region upstream of GTL2 in human renal cell carcinoma. Human Molecular Genetics 15, 821-830CrossRef Google Scholar PubMed

66Huang, J. et al. (2007) Up-regulation of DLK1 as an imprinted gene could contribute to human hepatocellular carcinoma. Carcinogenesis 28, 1094-1103CrossRef Google Scholar PubMed

67Gejman, R. et al. (2008) Selective loss of MEG3 expression and intergenic differentially methylated region hypermethylation in the MEG3/DLK1 locus in human clinically nonfunctioning pituitary adenomas. Journal of Clinical Endocrinology and Metabolism 93, 4119-4125CrossRef Google Scholar PubMed

68Benetatos, L. et al. (2008) Promoter hypermethylation of the MEG3 (DLK1/MEG3) imprinted gene in multiple myeloma. Clinical Lymphoma and Myeloma 8, 171-175CrossRef Google Scholar PubMed

69Benetatos, L. et al. (2010) CpG methylation analysis of the MEG3 and SNRPN imprinted genes in acute myeloid leukemia and myelodysplastic syndromes. Leukemia Research 34, 148-153CrossRef Google Scholar PubMed

70Zhao, J. et al. (2005) Hypermethylation of the promoter region is associated with the loss of MEG3 gene expression in human pituitary tumors. Journal of Clinical Endocrinology and Metabolism 90, 2179-2186CrossRef Google Scholar PubMed

71Savage, S.A. et al. (2007) Analysis of genes critical for growth regulation identifies insulin-like growth factor 2 receptor variations with possible functional significance as risk factors for osteosarcoma. Cancer Epidemiology, Biomarkers and Prevention 16, 1667-1674CrossRef Google Scholar PubMed

72Huang, Z. et al. (2006) High throughput detection of M6P/IGF2R intronic hypermethylation and LOH in ovarian cancer. Nucleic Acids Research 34, 555-563CrossRef Google Scholar PubMed

73Maegawa, S. et al. (2001) Epigenetic silencing of PEG3 gene expression in human glioma cell lines. Molecular Carcinogenesis 31, 1-9CrossRef Google Scholar PubMed

74Otsuka, S. et al. (2009) Aberrant promoter methylation and expression of the imprinted PEG3 gene in glioma. Proceedings of the Japan Academy – Series B: Physical and Biological Science 85, 157-165CrossRef Google Scholar PubMed

75Dowdy, S.C. et al. (2005) Biallelic methylation and silencing of paternally expressed gene 3 (PEG3) in gynecologic cancer cell lines. Gynecologic Oncology 99, 126-134CrossRef Google Scholar PubMed

76Kuerbitz, S.J. et al. (2002) Hypermethylation of the imprinted NNAT locus occurs frequently in pediatric acute leukemia. Carcinogenesis 23, 559-564CrossRef Google Scholar PubMed

77Revill, K. et al. (2009) Loss of neuronatin expression is associated with promoter hypermethylation in pituitary adenoma. Endocrine-related Cancer 16, 537-548CrossRef Google Scholar PubMed

78Li, J. et al. (2004) Imprinting of the human L3MBTL gene, a polycomb family member located in a region of chromosome 20 deleted in human myeloid malignancies. Proceedings of the National Academy of Sciences of the United States of America 101, 7341-7346CrossRef Google Scholar

79Kacem, S. and Feil, R. (2009) Chromatin mechanisms in genomic imprinting. Mammalian Genome 20, 544-556CrossRef Google Scholar PubMed

80Azuara, V. et al. (2006) Chromatin signatures of pluripotent cell lines. Nature Cell Biology 8, 532-538CrossRef Google Scholar PubMed

81Monk, D. et al. (2009) Reciprocal imprinting of human GRB10 in placental trophoblast and brain: evolutionary conservation of reversed allelic expression. Human Molecular Genetics 18, 3066-3074CrossRef Google Scholar PubMed

82Sanz, L.A. et al. (2008) A mono-allelic bivalent chromatin domain controls tissue-specific imprinting at Grb10. EMBO Journal 27, 2523-2532CrossRef Google Scholar PubMed

83McEwen, K.R. and Ferguson-Smith, A.C. (2010) Distinguishing epigenetic marks of developmental and imprinting regulation. Epigenetics and Chromatin 3, 2CrossRef Google Scholar PubMed

84Feinberg, A.P. and Vogelstein, B. (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301, 89-92CrossRef Google Scholar PubMed

85Fatemi, M. et al. (2001) The activity of the murine DNA methyltransferase Dnmt1 is controlled by interaction of the catalytic domain with the N-terminal part of the enzyme leading to an allosteric activation of the enzyme after binding to methylated DNA. Journal of Molecular Biology 309, 1189-1199CrossRef Google Scholar

86Weaver, J.R., Susiarjo, M. and Bartolomei, M.S. (2009) Imprinting and epigenetic changes in the early embryo. Mammalian Genome 20, 532-543CrossRef Google Scholar PubMed

87Li, X. et al. (2008) A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. Developmental Cell 15, 547-557CrossRef Google Scholar PubMed

88Mackay, D.J. et al. (2008) Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nature Genetics 40, 949-951CrossRef Google Scholar PubMed

89Nakamura, T. et al. (2007) PGC7/Stella protects against DNA demethylation in early embryogenesis. Nature Cell Biology 9, 64-71CrossRef Google Scholar PubMed

90Schoenherr, C.J., Levorse, J.M. and Tilghman, S.M. (2003) CTCF maintains differential methylation at the Igf2/H19 locus. Nature Genetics 33, 66-69CrossRef Google Scholar PubMed

91Rhee, I. et al. (2002) DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature 416, 552-556CrossRef Google Scholar PubMed

92Wu, S.C. and Zhang, Y. (2010) Active DNA demethylation: many roads lead to Rome. Nature Reviews. Molecular Cell Biology 11, 607-620CrossRef Google Scholar PubMed

93Lucci-Cordisco, E. and Neri, G. (2009) Silent beginning: early silencing of the MED1/MBD4 gene in colorectal tumorigenesis. Cancer Biology and Therapy 8, 192-193Google Scholar PubMed

94Tahiliani, M. et al. (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930-935CrossRef Google Scholar PubMed

95Sparmann, A. and van Lohuizen, M. (2006) Polycomb silencers control cell fate, development and cancer. Nature Reviews. Cancer 6, 846-856CrossRef Google Scholar PubMed

96Simon, J.A. and Kingston, R.E. (2009) Mechanisms of polycomb gene silencing: knowns and unknowns. Nature Reviews. Molecular Cell Biology 10, 697-708CrossRef Google Scholar

97Cao, R. et al. (2002) Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039-1043CrossRef Google Scholar PubMed

98Schwartz, Y.B. and Pirrotta, V. (2007) Polycomb silencing mechanisms and the management of genomic programmes. Nature Reviews. Genetics 8, 9-22CrossRef Google Scholar PubMed

99Wang, J. et al. (2001) Imprinted X inactivation maintained by a mouse polycomb group gene. Nature Genetics 28, 371-375CrossRef Google Scholar PubMed

100Pandey, R.R. et al. (2008) Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation. Molecular Cell 32, 232-246CrossRef Google Scholar PubMed

101Terranova, R. et al. (2008) Polycomb group proteins Ezh2 and Rnf2 direct genomic contraction and imprinted repression in early mouse embryos. Developmental Cell 15, 668-679CrossRef Google Scholar PubMed

102Redrup, L. et al. (2009) The long noncoding RNA Kcnq1ot1 organises a lineage-specific nuclear domain for epigenetic gene silencing. Development 136, 525-530CrossRef Google Scholar

103Bracken, A.P. and Helin, K. (2009) Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nature Reviews. Cancer 9, 773-784CrossRef Google Scholar PubMed

104Pasini, D. et al. (2008) Regulation of stem cell differentiation by histone methyltransferases and demethylases. Cold Spring Harbor Symppsia on Quantitative Biology 73, 253-263CrossRef Google Scholar PubMed

105Ohm, J.E. et al. (2007) A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nature Genetics 39, 237-242CrossRef Google Scholar PubMed

106Vire, E. et al. (2006) The polycomb group protein EZH2 directly controls DNA methylation. Nature 439, 871-874CrossRef Google Scholar PubMed

107Tiwari, V.K. et al. (2008) A novel 6C assay uncovers Polycomb-mediated higher order chromatin conformations. Genome Research 18, 1171-1179CrossRef Google Scholar PubMed

108Smallwood, A. et al. (2007) Functional cooperation between HP1 and DNMT1 mediates gene silencing. Genes and Development 21, 1169-1178CrossRef Google Scholar PubMed

109Esteve, P.O. et al. (2006) Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication. Genes and Development 20, 3089-3103CrossRef Google Scholar PubMed

110Tachibana, M. et al. (2008) G9a/GLP complexes independently mediate H3K9 and DNA methylation to silence transcription. EMBO Journal 27, 2681-2690CrossRef Google Scholar PubMed

111Wagschal, A. et al. (2008) G9a histone methyltransferase contributes to imprinting in the mouse placenta. Molecular and Cellular Biology 28, 1104-1113CrossRef Google Scholar PubMed

112Nagano, T. et al. (2008) The air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science 322, 1717-1720CrossRef Google Scholar PubMed

113Ueda, J. et al. (2006) Zinc finger protein Wiz links G9a/GLP histone methyltransferases to the co-repressor molecule CtBP. Journal of Biological Chemistry 281, 20120-20128CrossRef Google Scholar

114Huang, J. et al. (2010) G9a and Glp methylate lysine 373 in the tumor suppressor p53. Journal of Biological Chemistry 285, 9636-9641CrossRef Google Scholar PubMed

115Pannetier, M. et al. (2008) PR-SET7 and SUV4-20H regulate H4 lysine-20 methylation at imprinting control regions in the mouse. EMBO Report 9, 998-1005CrossRef Google Scholar PubMed

116Nielsen, S.J. et al. (2001) Rb targets histone H3 methylation and HP1 to promoters. Nature 412, 561-565CrossRef Google Scholar PubMed

117Sewalt, R.G. et al. (2002) Selective interactions between vertebrate polycomb homologs and the SUV39H1 histone lysine methyltransferase suggest that histone H3-K9 methylation contributes to chromosomal targeting of polycomb group proteins. Molecular and Cellular Biology 22, 5539-5553CrossRef Google Scholar PubMed

118Frontelo, P. et al. (2004) Suv39h histone methyltransferases interact with Smads and cooperate in BMP-induced repression. Oncogene 23, 5242-5251CrossRef Google Scholar PubMed

119Peters, A.H. et al. (2001) Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323-337CrossRef Google Scholar PubMed

120Ayton, P.M. and Cleary, M.L. (2001) Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 20, 5695-5707CrossRef Google Scholar PubMed

121Patel, A. et al. (2009) On the mechanism of multiple lysine methylation by the human mixed lineage leukemia protein-1 (MLL1) core complex. Journal of Biological Chemistry 284, 24242-24256CrossRef Google Scholar PubMed

122Esteve, P.O. et al. (2009) Regulation of DNMT1 stability through SET7-mediated lysine methylation in mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 106, 5076-5081CrossRef Google Scholar PubMed

123Ciccone, D.N. et al. (2009) KDM1B is a histone H3K4 demethylase required to establish maternal genomic imprints. Nature 461, 415-418CrossRef Google Scholar PubMed

124Wang, Y. et al. (2009) LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 138, 660-672CrossRef Google Scholar PubMed

125Zhang, Y. et al. (1999) Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. Genes and Development 13, 1924-1935CrossRef Google Scholar

126Reese, K.J. et al. (2007) Maintenance of paternal methylation and repression of the imprinted H19 gene requires MBD3. PLoS Genetics 3, e137CrossRef Google Scholar PubMed

127Klose, R.J. et al. (2007) The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 128, 889-900CrossRef Google Scholar PubMed

128Schotta, G. et al. (2004) A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes and Development 18, 1251-1262CrossRef Google Scholar PubMed

129Nishioka, K. et al. (2002) PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Molecular Cell 9, 1201-1213CrossRef Google Scholar PubMed

130Fraga, M.F. et al. (2005) Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nature Genetics 37, 391-400CrossRef Google Scholar PubMed

131Tryndyak, V.P., Kovalchuk, O. and Pogribny, I.P. (2006) Loss of DNA methylation and histone H4 lysine 20 trimethylation in human breast cancer cells is associated with aberrant expression of DNA methyltransferase 1, Suv4-20h2 histone methyltransferase and methyl-binding proteins. Cancer Biology and Therapy 5, 65-70CrossRef Google Scholar PubMed

132Wu, M.Y., Tsai, T.F. and Beaudet, A.L. (2006) Deficiency of Rbbp1/Arid4a and Rbbp1l1/Arid4b alters epigenetic modifications and suppresses an imprinting defect in the PWS/AS domain. Genes and Development 20, 2859-2870CrossRef Google Scholar PubMed

133Zhao, Q. et al. (2009) PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing. Nature Structural and Molecular Biology 16, 304-311CrossRef Google Scholar PubMed

134Jelinic, P., Stehle, J.C. and Shaw, P. (2006) The testis-specific factor CTCFL cooperates with the protein methyltransferase PRMT7 in H19 imprinting control region methylation. PLoS Biology 4, e355CrossRef Google Scholar PubMed

135Ohlsson, R., Lobanenkov, V. and Klenova, E. (2010) Does CTCF mediate between nuclear organization and gene expression? Bioessays 32, 37-50CrossRef Google Scholar PubMed

136Nguyen, P. et al. (2008) CTCFL/BORIS is a methylation-independent DNA-binding protein that preferentially binds to the paternal H19 differentially methylated region. Cancer Research 68, 5546-5551CrossRef Google Scholar

137Zilberman, D. et al. (2008) Histone H2A.Z and DNA methylation are mutually antagonistic chromatin marks. Nature 456, 125-129CrossRef Google Scholar PubMed

138Barski, A. et al. (2007) High-resolution profiling of histone methylations in the human genome. Cell 129, 823-837CrossRef Google Scholar PubMed

139Costanzi, C. et al. (2000) Histone macroH2A1 is concentrated in the inactive X chromosome of female preimplantation mouse embryos. Development 127, 2283-2289CrossRef Google Scholar PubMed

140Choo, J.H. et al. (2006) Allele-specific deposition of macroH2A1 in imprinting control regions. Human Molecular Genetics 15, 717-724CrossRef Google Scholar PubMed

141Rasmussen, T.P. et al. (1999) Messenger RNAs encoding mouse histone macroH2A1 isoforms are expressed at similar levels in male and female cells and result from alternative splicing. Nucleic Acids Research 27, 3685-3689CrossRef Google Scholar PubMed

142Zhang, R. et al. (2005) Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Developmental Cell 8, 19-30CrossRef Google Scholar PubMed

143Sporn, J.C. et al. (2009) Histone macroH2A isoforms predict the risk of lung cancer recurrence. Oncogene 28, 3423-3428CrossRef Google Scholar PubMed

144Nativio, R. et al. (2009) Cohesin is required for higher-order chromatin conformation at the imprinted IGF2-H19 locus. PLoS Genetics 5, e1000739CrossRef Google Scholar PubMed

145Vu, T.H., Nguyen, A.H. and Hoffman, A.R. (2010) Loss of IGF2 imprinting is associated with abrogation of long-range intrachromosomal interactions in human cancer cells. Human Molecular Genetics 19, 901-919CrossRef Google Scholar PubMed

146Hadjur, S. et al. (2009) Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature 460, 410-413CrossRef Google Scholar PubMed

147Mishiro, T. et al. (2009) Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster. EMBO Journal 28, 1234-1245CrossRef Google Scholar PubMed

148Taft, R.J. et al. (2010) Non-coding RNAs: regulators of disease. Journal of Pathology 220, 126-139CrossRef Google Scholar PubMed

149Ng, K. et al. (2007) Xist and the order of silencing. EMBO Report 8, 34-39CrossRef Google Scholar PubMed

150Sleutels, F., Zwart, R. and Barlow, D.P. (2002) The non-coding Air RNA is required for silencing autosomal imprinted genes. Nature 415, 810-813CrossRef Google Scholar PubMed

151Thakur, N. et al. (2004) An antisense RNA regulates the bidirectional silencing property of the Kcnq1 imprinting control region. Molecular and Cellular Biology 24, 7855-7862CrossRef Google Scholar PubMed

152Williamson, C.M. et al. (2006) Identification of an imprinting control region affecting the expression of all transcripts in the Gnas cluster. Nature Genetics 38, 350-355CrossRef Google Scholar PubMed

153Le Meur, E. et al. (2005) Dynamic developmental regulation of the large non-coding RNA associated with the mouse 7C imprinted chromosomal region. Developmental Biology 286, 587-600CrossRef Google Scholar PubMed

154Peters, J. and Robson, J.E. (2008) Imprinted noncoding RNAs. Mammalian Genome 19, 493-502CrossRef Google Scholar PubMed

155Latos, P.A. and Barlow, D.P. (2009) Regulation of imprinted expression by macro non-coding RNAs. RNA Biology 6, 100-106CrossRef Google Scholar PubMed

156Wang, X. et al. (2008) Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription. Nature 454, 126-130CrossRef Google Scholar PubMed

157Hudson, Q.J. et al. (2010) Genomic imprinting mechanisms in embryonic and extraembryonic mouse tissues. Heredity 105, 45-56CrossRef Google Scholar PubMed

158Yu, W. et al. (2008) Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 451, 202-206CrossRef Google Scholar PubMed

159Morris, K.V. et al. (2008) Bidirectional transcription directs both transcriptional gene activation and suppression in human cells. PLoS Genetics 4, e1000258CrossRef Google Scholar PubMed

160Watanabe, T. et al. (2008) Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 453, 539-543CrossRef Google Scholar PubMed

161Tam, O.H. et al. (2008) Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature 453, 534-538CrossRef Google Scholar PubMed

162Guttman, M. et al. (2009) Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature 458, 223-227CrossRef Google Scholar

163Khalil, A.M. et al. (2009) Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proceedings of the National Academy of Sciences of the United States of America 106, 11667-11672CrossRef Google Scholar PubMed

164Gupta, R.A. et al. (2010) Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071-1076CrossRef Google Scholar PubMed

165Yoshimizu, T. et al. (2008) The H19 locus acts in vivo as a tumor suppressor. Proceedings of the National Academy of Sciences of the United States of America 105, 12417-12422CrossRef Google Scholar PubMed

166Tsang, W.P. et al. (2010) Oncofetal H19-derived miR-675 regulates tumor suppressor RB in human colorectal cancer. Carcinogenesis 31, 350-358CrossRef Google Scholar PubMed

167Zhou, Y. et al. (2007) Activation of p53 by MEG3 non-coding RNA. Journal of Biological Chemistry 282, 24731-24742CrossRef Google Scholar PubMed

168Zhang, X. et al. (2010) Maternally expressed gene 3 (MEG3) noncoding ribonucleic acid: isoform structure, expression, and functions. Endocrinology 151, 939-947CrossRef Google Scholar PubMed

169Baek, D. et al. (2008) The impact of microRNAs on protein output. Nature 455, 64-71CrossRef Google Scholar PubMed

170Seitz, H. et al. (2004) A large imprinted microRNA gene cluster at the mouse Dlk1-Gtl2 domain. Genome Research 14, 1741-1748CrossRef Google Scholar PubMed

171Glazov, E.A. et al. (2008) Origin, evolution, and biological role of miRNA cluster in DLK-DIO3 genomic region in placental mammals. Molecular Biology and Evolution 25, 939-948CrossRef Google Scholar PubMed

172Saito, Y. et al. (2006) Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 9, 435-443CrossRef Google Scholar PubMed

173Lee, J.W. et al. (2008) Altered MicroRNA expression in cervical carcinomas. Clinical Cancer Research 14, 2535-2542CrossRef Google Scholar PubMed

174Yu, J. et al. (2006) Human microRNA clusters: genomic organization and expression profile in leukemia cell lines. Biochemical and Biophysical Research Communications 349, 59-68CrossRef Google Scholar PubMed

175Guo, L. et al. (2010) Gene expression profiling of drug-resistant small cell lung cancer cells by combining microRNA and cDNA expression analysis. European Journal of Cancer 46, 1692-1702CrossRef Google Scholar PubMed

176Guled, M. et al. (2009) CDKN2A, NF2, and JUN are dysregulated among other genes by miRNAs in malignant mesothelioma – a miRNA microarray analysis. Genes, Chromosomes and Cancer 48, 615-623CrossRef Google Scholar PubMed

177Veronese, A. et al. (2010) Oncogenic role of miR-483-3p at the IGF2/483 locus. Cancer Research 70, 3140-3149CrossRef Google Scholar PubMed

178Malzkorn, B. et al. (2009) Identification and functional characterization of microRNAs involved in the malignant progression of gliomas. Brain Pathology 20, 539-550CrossRef Google Scholar

179Wong, T.S. et al. (2008) Mature miR-184 as potential oncogenic microRNA of squamous cell carcinoma of tongue. Clinical Cancer Research 14, 2588-2592CrossRef Google Scholar PubMed

180Liu, C. et al. (2010) Epigenetic regulation of miR-184 by MBD1 governs neural stem cell proliferation and differentiation. Cell Stem Cell 6, 433-444CrossRef Google Scholar PubMed

181Stubbs, M. and Griffiths, J.R. (2010) The altered metabolism of tumors: HIF-1 and its role in the Warburg effect. Advances in Enzyme Regulation 50, 44-55CrossRef Google Scholar PubMed

182Timp, W., Levchenko, A. and Feinberg, A.P. (2009) A new link between epigenetic progenitor lesions in cancer and the dynamics of signal transduction. Cell Cycle 8, 383-390CrossRef Google Scholar PubMed

183Young, A.R. and Narita, M. (2009) SASP reflects senescence. EMBO Report 10, 228-230CrossRef Google Scholar PubMed

184Tezuka, N., Brown, A.M. and Yanagawa, S. (2007) GRB10 binds to LRP6, the Wnt co-receptor and inhibits canonical Wnt signaling pathway. Biochemical and Biophysical Research Communications 356, 648-654CrossRef Google Scholar PubMed

185Jiang, X. et al. (2010) The imprinted gene PEG3 inhibits Wnt signaling and regulates glioma growth. Journal of Biological Chemistry 285, 8472-8480CrossRef Google Scholar PubMed

186Kobayashi, S. et al. (2002) Paternal expression of a novel imprinted gene, Peg12/Frat3, in the mouse 7C region homologous to the Prader–Willi syndrome region. Biochemical and Biophysical Research Communications 290, 403-408CrossRef Google Scholar

187Jubb, A.M. et al. (2006) Achaete-scute like 2 (ascl2) is a target of Wnt signalling and is upregulated in intestinal neoplasia. Oncogene 25, 3445-3457CrossRef Google Scholar PubMed

188Zhu, W. et al. (2008) IGFBP-4 is an inhibitor of canonical Wnt signalling required for cardiogenesis. Nature 454, 345-349CrossRef Google Scholar PubMed

189Wick, K.R. et al. (2003) Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptor. Journal of Biological Chemistry 278, 8460-8467CrossRef Google Scholar PubMed

190Langlais, P. et al. (2004) Negative regulation of insulin-stimulated mitogen-activated protein kinase signaling by Grb10. Molecular Endocrinology 18, 350-358CrossRef Google Scholar PubMed

191Charalambous, M. et al. (2010) Maternally-inherited Grb10 reduces placental size and efficiency. Developmental Biology 337, 1-8CrossRef Google Scholar

192Playford, M.P. et al. (2000) Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of beta-catenin. Proceedings of the National Academy of Sciences of the United States of America 97, 12103-12108CrossRef Google Scholar PubMed

193Wade, M., Wang, Y.V. and Wahl, G.M. (2010) The p53 orchestra: Mdm2 and Mdmx set the tone. Trends in Cell Biology 20, 299-309CrossRef Google Scholar PubMed

194Kaghad, M. et al. (1997) Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90, 809-819CrossRef Google Scholar PubMed

195Kim, J.W. et al. (2008) TIP60 represses transcriptional activity of p73beta via an MDM2-bridged ternary complex. Journal of Biological Chemistry 283, 20077-20086CrossRef Google Scholar PubMed

196Yu, Y. et al. (2006) Biochemistry and biology of ARHI (DIRAS3), an imprinted tumor suppressor gene whose expression is lost in ovarian and breast cancers. Methods in Enzymology 407, 455-468CrossRef Google Scholar PubMed

197Nishimoto, A. et al. (2005) A Ras homologue member I directly inhibits signal transducers and activators of transcription 3 translocation and activity in human breast and ovarian cancer cells. Cancer Research 65, 6701-6710CrossRef Google Scholar PubMed

198Huang, S. et al. (2010) ARHI (DIRAS3), an imprinted tumour suppressor gene, binds to importins and blocks nuclear import of cargo proteins. Bioscience Reports 30, 159-168CrossRef Google Scholar

199Ferres-Marco, D. et al. (2006) Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing. Nature 439, 430-436CrossRef Google Scholar PubMed

200Bray, S.J. et al. (2008) The atypical mammalian ligand Delta-like homologue 1 (Dlk1) can regulate Notch signalling in Drosophila. BMC Developmental Biology 8, 11CrossRef Google Scholar PubMed

201Ikushima, H. and Miyazono, K. (2010) TGFbeta signalling: a complex web in cancer progression. Nature Reviews. Cancer 10, 415-424CrossRef Google Scholar PubMed

202Bergstrom, R. et al. (2010) Transforming growth factor beta promotes complexes between Smad proteins and CTCF on the H19 imprinting control region chromatin. Journal of Biological Chemistry 285, 19727-19737CrossRef Google Scholar PubMed

203Scandura, J.M. et al. (2004) Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation. Proceedings of the National Academy of Sciences of the United States of America 101, 15231-15236CrossRef Google Scholar PubMed

204Lux, A. et al. (2005) Human retroviral gag- and gag-pol-like proteins interact with the transforming growth factor-beta receptor activin receptor-like kinase 1. Journal of Biological Chemistry 280, 8482-8493CrossRef Google Scholar PubMed

205Li, C.M. et al. (2006) PEG10 is a c-MYC target gene in cancer cells. Cancer Research 66, 665-672CrossRef Google Scholar PubMed

206Okabe, H. et al. (2003) Involvement of PEG10 in human hepatocellular carcinogenesis through interaction with SIAH1. Cancer Research 63, 3043-3048Google Scholar PubMed

207Zhang, P. et al. (1998) Cooperation between the Cdk inhibitors p27(KIP1) and p57(KIP2) in the control of tissue growth and development. Genes and Development 12, 3162-3167CrossRef Google Scholar PubMed

208Montgomery, S.B. et al. (2010) Transcriptome genetics using second generation sequencing in a Caucasian population. Nature 464, 773-777CrossRef Google Scholar

209Dawson, M.A. et al. (2009) JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature 461, 819-822CrossRef Google Scholar PubMed

210Saito, Y. and Jones, P.A. (2006) Epigenetic activation of tumor suppressor microRNAs in human cancer cells. Cell Cycle 5, 2220-2222CrossRef Google Scholar PubMed

211Klisovic, R.B. et al. (2008) A phase I biological study of MG98, an oligodeoxynucleotide antisense to DNA methyltransferase 1, in patients with high-risk myelodysplasia and acute myeloid leukemia. Clinical Cancer Research 14, 2444-2449CrossRef Google Scholar PubMed

212Ptak, C. and Petronis, A. (2008) Epigenetics and complex disease: from etiology to new therapeutics. Annual Review of Pharmacology and Toxicology 48, 257-276CrossRef Google Scholar PubMed

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