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Human Molecular Genetics Advance Access originally published online on January 7, 2005
Human Molecular Genetics 2005 14(4):503-511; doi:10.1093/hmg/ddi047
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Human Molecular Genetics, Vol. 14, No. 4 © Oxford University Press 2005; all rights reserved

The two-domain hypothesis in Beckwith–Wiedemann syndrome: autonomous imprinting of the telomeric domain of the distal chromosome 7 cluster

Flavia Cerrato1,{dagger}, Angela Sparago1, Ines Di Matteo1, Xiangang Zou2, Wendy Dean3, Hiroyuki Sasaki4, Paul Smith3, Rita Genesio5, Marianne Bruggemann2, Wolf Reik3 and Andrea Riccio1,*,{dagger}

1Dipartimento di Scienze Ambientali, Seconda Università di Napoli, via Vivaldi 43, 81100 Caserta, Italy, 2Laboratory of Developmental Immunology, 3Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB2 4AT, UK, 4Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Research Organization of Information and Systems and Department of Genetics, School of Life Science, Graduate University for Advanced Studies, 1111 Yata, Mishima, Shizuoka 411-8540, Japan and 5Dipartimento di Biologia e Patologia Cellulare e Molecolare ‘L. Califano’, Università di Napoli ‘Federico II’, Napoli, Italy

Received November 8, 2004; Accepted December 21, 2004

A large cluster of imprinted genes is located on the mouse distal chromosome 7. This cluster is well conserved in humans and its dysregulation results in the overgrowth- and tumour-associated Beckwith–Wiedemann syndrome. Two imprinting centres (IC1 and IC2) controlling different sets of genes have been identified in the cluster, raising the hypothesis that the cluster is divided into two functionally independent domains. However, the mechanisms by which imprinting of genes in the IC2 domain (e.g. Cdkn1c and Kcnq1) is regulated have not been well defined, and recent evidence indicates that distantly located cis-acting elements are required for IC2 imprinting. We show that the maternal germ-line methylation at IC2 and the imprinted expression of five genes of the IC2 domain are correctly reproduced on an 800 kb YAC transgene when transferred outside of their normal chromosomal context. These results, together with previous transgenic studies, locate key imprinting control elements within a 400 kb region centromeric of IC2 and demonstrate that each of the two domains of the cluster contains the cis-acting elements required for the imprinting control of its own genes. Finally, maternal, but not paternal, transmission of the transgene results in fetal growth restriction, suggesting that during evolution the acquisition of imprinting may have been facilitated by the opposite effects of the two domains on embryo growth.

* To whom correspondence should be addressed. Tel: +39 823274599; Email: andrea.riccio{at}unina2.it


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