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Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta

Oncogene volume 26, pages 2518–2524 (2007)Cite this article

Abstract

In human post-natal somatic cells, low global levels of DNA methylation have been associated with the hypomethylation of several repetitive elements, a feature that has been proposed to be a surrogate epigenetic marker. These data, mainly derived from the analysis of cancer cells, suggest a potential association between loss of cell-growth control and altered differentiation with hypomethylation of repetitive sequences. Partial hydatidiform moles (PHMs) can be used as an alternative model for investigating this association in a non-tumorigenic context. This gestational disease is characterized by abnormal overgrowth and differentiation of the placenta and spontaneous abortion. Here, we comprehensively analyse the DNA methylation of these trophoblastic tissues in both PHM and normal placenta at global and sequence-specific levels. Analysis of the global 5-methylcytosine content and immunohistochemistry indicate that PHM and normal placenta have identical global levels of DNA methylation. In contrast, bisulfite genomic sequencing shows that, whereas Alu, NBL2 and satellite 2 repetitive elements are equally methylated, LINE-1 sequences are hypermethylated in PHM tissues (∼2-fold relative to normal placenta). Interestingly, altered demethylation is also found in triploid diandric embryos that originate from dispermic fertilization of an oocyte, a common event responsible for most PHMs. In conclusion, alterations of DNA methylation do not seem to be randomly distributed in PHM, as several repeated elements remain unaltered, whereas LINE-1 sequences are hypermethylated. In addition, our findings suggest that the hypomethylation of repetitive elements in cancer is directly linked to the neoplasic process and not a simple consequence of loss of growth control observed in most of the cancer cells.

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References

  • Bariol C, Suter C, Cheong K, Ku SL, Meagher A, Hawkins N et al. (2003). The relationship between hypomethylation and CpG island methylation in colorectal neoplasia. Am J Pathol 162: 1361–1371.

    Article  CAS  Google Scholar 

  • Baylin SB . (2005). DNA methylation and gene silencing in cancer. Nat Clin Pract Oncol 2 (Suppl 1): S4–S11.

    Article  CAS  Google Scholar 

  • Chalitchagorn K, Shuangshoti S, Hourpai N, Kongruttanachok N, Tangkijvanich P, Thong-ngam D et al. (2004). Distinctive pattern of LINE-1 methylation level in normal tissues and the association with carcinogenesis. Oncogene 23: 8841–8846.

    Article  CAS  Google Scholar 

  • Chen H, Ye D, Xie X, Lu W, Zhu C, Chen X . (2005). PTEN promoter methylation and protein expression in normal early placentas and hydatidiform moles. J Soc Gynecol Investig 12: 214–217.

    Article  CAS  Google Scholar 

  • Ehrlich M . (2002). DNA methylation in cancer: too much, but also too little. Oncogene 21: 5400–5413.

    Article  CAS  Google Scholar 

  • Esteller M . (2005). Aberrant DNA methylation as a cancer-inducing mechanism. Annu Rev Pharmacol Toxicol 45: 629–656.

    Article  CAS  Google Scholar 

  • Feinberg AP, Gehrke CW, Kuo KC, Ehrlich M . (1988). Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res 48: 1159–1161.

    CAS  Google Scholar 

  • Fraga MF, Esteller M . (2002). DNA methylation: a profile of methods and applications. Biotechniques 33: 636–649.

    Article  Google Scholar 

  • Gama-Sosa MA, Midgett RM, Slagel VA, Githens S, Kuo KC, Gehrke CW et al. (1983a). Tissue-specific differences in DNA methylation in various mammals. Biochim Biophys Acta 740: 212–219.

    Article  CAS  Google Scholar 

  • Gama-Sosa MA, Wang RY, Kuo KC, Gehrke CW, Ehrlich M . (1983b). The 5-methylcytosine content of highly repeated sequences in human DNA. Nucleic Acids Res 11: 3087–3095.

    Article  CAS  Google Scholar 

  • Genest DR . (2001). Partial hydatidiform mole: clinicopathological features, differential diagnosis, ploidy and molecular studies, and gold standards for diagnosis. Int J Gynecol Pathol 20: 315–322.

    Article  CAS  Google Scholar 

  • Ghabreau L, Roux JP, Niveleau A, Fontaniere B, Mahe C, Mokni M et al. (2004). Correlation between the DNA global methylation status and progesterone receptor expression in normal endometrium, endometrioid adenocarcinoma and precursors. Virchows Arch 445: 129–134.

    Article  CAS  Google Scholar 

  • Hjelle BL, Phillips III JA, Seeburg PH . (1982). Relative levels of methylation in human growth hormone and chorionic somatomammotropin genes in expressing and non-expressing tissues. Nucleic Acids Res 10: 3459–3474.

    Article  CAS  Google Scholar 

  • Hoffmann MJ, Schulz WA . (2005). Causes and consequences of DNA hypomethylation in human cancer. Biochem Cell Biol 83: 296–321.

    Article  CAS  Google Scholar 

  • Issa JP . (2004). CpG island methylator phenotype in cancer. Nat Rev Cancer 4: 988–993.

    Article  CAS  Google Scholar 

  • Jackson K, Yu MC, Arakawa K, Fiala E, Youn B, Fiegl H et al. (2004). DNA hypomethylation is prevalent even in low-grade breast cancers. Cancer Biol Ther 3: 1225–1231.

    Article  CAS  Google Scholar 

  • Jeanpierre M . (1994). Human satellites 2 and 3. Ann Genet 37: 163–1671.

    CAS  PubMed  Google Scholar 

  • Judson H, Hayward BE, Sheridan E, Bonthron DT . (2002). A global disorder of imprinting in the human female germ line. Nature 416: 539–542.

    Article  CAS  Google Scholar 

  • Lee C, Wevrick R, Fisher RB, Ferguson-Smith MA, Lin CC . (1997). Human centromeric DNAs. Hum Genet 100: 291–304.

    Article  CAS  Google Scholar 

  • Magdinier F, Billard LM, Wittmann G, Frappart L, Benchaib M, Lenoir GM et al. (2000). Regional methylation of the 5′ end CpG island of BRCA1 is associated with reduced gene expression in human somatic cells. FASEB J 14: 1585–1594.

    CAS  PubMed  Google Scholar 

  • Magdinier F, D’Estaing SG, Peinado C, Demirci B, Berthet C, Guerin JF et al. (2002). Epigenetic marks at BRCA1 and p53 coding sequences in early human embryogenesis. Mol Hum Reprod 8: 630–635.

    Article  CAS  Google Scholar 

  • Magdinier F, Ribieras S, Lenoir GM, Frappart L, Dante R . (1998). Down-regulation of BRCA1 in human sporadic breast cancer; analysis of DNA methylation patterns of the putative promoter region. Oncogene 17: 3169–3176.

    Article  CAS  Google Scholar 

  • Morgan HD, Santos F, Green K, Dean W, Reik W . (2005). Epigenetic reprogramming in mammals. Hum Mol Genet 14 (Spec No. 1): R47–R58.

    Article  CAS  Google Scholar 

  • Nishiyama R, Qi L, Lacey M, Ehrlich M . (2005). Both hypomethylation and hypermethylation in a 0.2-kb region of a DNA repeat in cancer. Mol Cancer Res 3: 617–626.

    Article  CAS  Google Scholar 

  • Rollins RA, Haghighi F, Edwards JR, Das R, Zhang MQ, Ju J et al. (2006). Large-scale structure of genomic methylation patterns. Genome Res 16: 157–163.

    Article  CAS  Google Scholar 

  • Tavassoli FA, Devilee P . (2003). World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Breast and Female Genital Organs. IARC Press: Lyon, France.

    Google Scholar 

  • Tsien F, Fiala ES, Youn B, Long TI, Laird PW, Weissbecker K et al. (2002). Prolonged culture of normal chorionic villus cells yields ICF syndrome-like chromatin decondensation and rearrangements. Cytogenet Genome Res 98: 13–21.

    Article  CAS  Google Scholar 

  • Weisenberger DJ, Campan M, Long TI, Kim M, Woods C, Fiala E et al. (2005). Analysis of repetitive element DNA methylation by MethyLight. Nucleic Acids Res 33: 6823–6836.

    Article  CAS  Google Scholar 

  • Widschwendter M, Jiang G, Woods C, Muller HM, Fiegl H, Goebel G et al. (2004). DNA hypomethylation and ovarian cancer biology. Cancer Res 64: 4472–4480.

    Article  CAS  Google Scholar 

  • Yang AS, Estecio MR, 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 323: e38.

    Article  Google Scholar 

  • Young LE, Beaujean N . (2004). DNA methylation in the preimplantation embryo: the differing stories of the mouse and sheep. Anim Reprod Sci 82–83: 61–78.

    Article  Google Scholar 

  • Zaragoza MV, Surti U, Redline RW, Millie E, Chakravarti A, Hassold TJ . (2000). Parental origin and phenotype of triploidy in spontaneous abortions: predominance of diandry and association with the partial hydatidiform mole. Am J Hum Genet 66: 1807–1820.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Nabiha Missaoui for her help with the immunochemical analysis, and to Dr Jacqueline Lornage and the members of the Laboratory of Reproductive Biology team for collecting human gametes and triploid embryos. We also thank Dr A Niveleau for the generous gift of anti-5-MeCyt antibodies. The present work was supported by the Ligue Nationale contre le Cancer (Comité du Rhône); the Association pour la Recherche sur le Cancer; Organon, Serifontaine, France; the Institut National de la Santé et de la Recherche Médicale (Réseau Développement Embryonnaire) and the Institut National contre le Cancer (EpiPro).

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Authors and Affiliations

  1. Unité INSERM 590, Laboratoire d’Oncologie Moléculaire, Centre Léon Bérard, Lyon Cedex, France

    D Perrin & R Dante

  2. Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Madrid, Spain

    E Ballestar, M F Fraga & M Esteller

  3. Laboratoire d’Anatomie Pathologie, Hôpital Edouard Herriot, Lyon, France

    L Frappart

  4. Laboratoire de Biologie de la Reproduction et du Développement, UCBL1, Lyon Cedex, France

    J-F Guerin

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  1. D Perrin
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  2. E Ballestar
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  4. L Frappart
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  7. R Dante
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Correspondence to R Dante.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Perrin, D., Ballestar, E., Fraga, M. et al. Specific hypermethylation of LINE-1 elements during abnormal overgrowth and differentiation of human placenta. Oncogene 26, 2518–2524 (2007). https://doi.org/10.1038/sj.onc.1210039

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