Nucleic Acids Research Advance Access originally published online on September 29, 2006
Nucleic Acids Research 2006 34(19):5438-5448; doi:10.1093/nar/gkl657
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Nucleic Acids Research, 2006, Vol. 34, No. 19 5438-5448
© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Molecular Biology |
Non-random, individual-specific methylation profiles are present at the sixth CTCF binding site in the human H19/IGF2 imprinting control region
Laboratoire d'Epigénétique, Centre National de Génotypage 2 rue Gaston Crémieux, 91000 Evry, France 1Génomique et Epigénétique des Pathologies Placentaires (GEPP) INSERM U567 and UMR CNRS 8104, Hôpital Cochin and Université Paris V-René Descartes 24 rue du Faubourg St Jacques, 75014 Paris, France 2Département PHASE, Institut National de la Recherche Agronomique INRA, France 3Laboratoire d'Histologie, Embryologie, Cytogénétique, Faculté de Médecine, APHP, Hôpital Cochin 123 Boulevard de Port-Royal, 75014 Paris, France 4Faculté de Médecine, Université de la Méditerrannée et Service de Néonatologie, Hôpital de la Conception, AP-HM 147 Boulevard de la Baille, 13385 Marseille, France 5Service de Gynécologie Obstétrique, Hôpital St Antoine 184, rue du Faubourg St-Antoine, 75012 Paris, France 6Service de Gynécologie Obstétrique, APHP, Hôpital Cochin 123 Boulevard de Port-Royal, 75014 Paris, France 7Animal Genetics Department, Institut National de la Recherche Agronomique INRA, France
*To whom correspondence should be addressed at Groupleader Epigenetics, Centre National de Génotypage, Bâtiment G2, 2 rue Gaston Crémieux, CP5721, 91057 Evry, France. Tel: +33 1 6087 8423; Fax: +33 1 6087 8485; Email: tost{at}cng.fr
Received July 21, 2006. Revised August 25, 2006. Accepted August 25, 2006.
Expression of imprinted genes is classically associated with differential methylation of specific CpG-rich DNA regions (DMRs). The H19/IGF2 locus is considered a paradigm for epigenetic regulation. In mice, as in humans, the essential H19 DMR—target of the CTCF insulator—is located between the two genes. Here, we performed a pyrosequencing-based quantitative analysis of its CpG methylation in normal human tissues. The quantitative analysis of the methylation level in the H19 DMR revealed three unexpected discrete, individual-specific methylation states. This epigenetic polymorphism was confined to the sixth CTCF binding site while a unique median-methylated profile was found at the third CTCF binding site as well as in the H19 promoter. Monoallelic expression of H19 and IGF2 was maintained independently of the methylation status at the sixth CTCF binding site and the IGF2 DMR2 displayed a median-methylated profile in all individuals and tissues analyzed. Interestingly, the methylation profile was genetically transmitted. Transgenerational inheritance of the H19 methylation profile was compatible with a simple model involving one gene with three alleles. The existence of three individual-specific epigenotypes in the H19 DMR in a non-pathological situation means it is important to reconsider the diagnostic value and functional importance of the sixth CTCF binding site.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
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