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Human Molecular Genetics Advance Access published online on January 7, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi047
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Human Molecular Genetics © Oxford University Press 2005; all rights reserved

Article

The two-domain hypothesis in Beckwith-Wiedemann Syndrome: Autonomous imprinting of the telomeric domain of the distal chromosome 7 cluster

Flavia Cerrato 1, Angela Sparago 2, Ines Di Matteo 2, Xiangang Zou 3, Wendy Dean 4, Hiroyuki Sasaki 5, Paul Smith 4, Rita Genesio 6, Marianne Bruggemann 3, Wolf Reik 4, and Andrea Riccio 1*

1 Dipartimento di Scienze Ambientali, Seconda Università di Napoli, via Vivaldi 43, 81100 Caserta, Italy; The Babraham Institute, Cambridge, UK
2 Dipartimento di Scienze Ambientali, Seconda Università di Napoli, via Vivaldi 43, 81100 Caserta, Italy
3 Laboratory of Developmental Immunology, The Babraham Institute, Cambridge CB2 4AT, United Kingdom
4 Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB2 4AT, United Kingdom
5 Division 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
6 Dipartimento di Biologia e Patologia Cellulare e Molecolare "L. Califano", Università di Napoli "Federico II", Napoli, Italy

* To whom correspondence should be addressed.
Andrea Riccio, E-mail: andrea.riccio{at}unina2.it


  Abstract

A large cluster of imprinted genes is located on mouse distal chromosome 7. This cluster is well conserved in humans and its dysregulation results in the overgrowth- and tumour-associated Beckwith-Wiedemann Syndrome (BWS). 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 in two functionally independent domains. However, the mechanisms by which imprinting of genes in the IC2 domain (e.g. Cdkn1d, 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 germline 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.


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