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Human Molecular Genetics, 2003, Vol. 12, No. 3 295-305
© 2003 Oxford University Press

Epigenetic modifications in an imprinting cluster are controlled by a hierarchy of DMRs suggesting long-range chromatin interactions

Susana Lopes1,{dagger}, Annabelle Lewis1,{dagger}, Petra Hajkova2, Wendy Dean1, Joachim Oswald2, Thierry Forné3, Adele Murrell1, Miguel Constância1, Marisa Bartolomei4, Jörn Walter2 and Wolf Reik1,*

1Laboratory of Developmental Genetics and Imprinting, Developmental Genetics Programme, The Babraham Institute, Cambridge CB2 4AT, UK, 2Universität des Saarlandes, Fr 8.2 Genetik, 66041 Saarbrücken, Germany, 3Institut de Génétique Moléculaire de Montpellier, Montpellier, France and 4Howard Hughes Medical Institute and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA

Received September 20, 2002; Accepted November 22, 2002

Imprinted genes and their control elements occur in clusters in the mammalian genome and carry epigenetic modifications. Observations from imprinting disorders suggest that epigenetic modifications throughout the clusters could be under regional control. However, neither the elements that are responsible for regional control, nor its developmental timing, particularly whether it occurs in the germline or postzygotically, are known. Here we examine regional control of DNA methylation in the imprinted Igf2-H19 region in the mouse. Paternal germline specific methylation was reprogrammed after fertilization in two differentially methylated regions (DMRs) in Igf2, and was reestablished after implantation. Using a number of knockout strains in the region, we found that the DMRs themselves are involved in regional coordination in a hierarchical fashion. Thus the H19 DMR was needed on the maternal allele to protect the Igf2 DMRs 1 and 2 from methylation, and Igf2 DMR1 was needed to protect DMR2 from methylation. This regional coordination occurred exclusively after fertilization during somatic development, and did not involve linear spreading of DNA methylation, suggesting a model in which long-range chromatin interactions are involved in regional epigenetic coordination. These observations are likely to be relevant to other gene clusters in which epigenetic regulation plays a role, and in pathological situations in which epigenetic regulation is disrupted.

* To whom correspondence should be addressed. Tel: +44 1223496338; Fax: +44 1223496015; Email: wolf.reik{at}bbsrc.ac.uk

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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