title: The two-domain hypothesis in Beckwith-Wiedemann syndrome: autonomous imprinting of the telomeric domain of the distal chromosome 7 cluster.
abstract: 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.
authors.affiliation: Dipartimento di Scienze Ambientali, Seconda Università di Napoli, via Vivaldi 43, 81100 Caserta, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Cerrato
authors.forename: Angela
authors.initials: A
authors.lastname: Sparago
authors.forename: Ines
authors.initials: I
authors.lastname: Di Matteo
authors.forename: Xiangang
authors.initials: X
authors.lastname: Zou
authors.forename: Wendy
authors.initials: W
authors.lastname: Dean
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sasaki
authors.forename: Paul
authors.initials: P
authors.lastname: Smith
authors.forename: Rita
authors.initials: R
authors.lastname: Genesio
authors.forename: Marianne
authors.initials: M
authors.lastname: Bruggemann
authors.forename: Wolf
authors.initials: W
authors.lastname: Reik
authors.forename: Andrea
authors.initials: A
authors.lastname: Riccio
mesh_terms: D000818:Animals; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D002503:Centromere; D018244:Chromosomes, Artificial, Yeast; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D050761:Cyclin-Dependent Kinase Inhibitor p57; D019175:DNA Methylation; D004622:Embryo, Mammalian / Q000166:cytology / Q000502:physiology; D004791:Enzyme Inhibitors; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D020868:Gene Silencing / Q000502:physiology; D018392:Genomic Imprinting; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics; D017434:Protein Structure, Tertiary; D016615:Telomere / Q000235:genetics*; D019076:Transgenes / Q000502:physiology
chemical_list: C493964:CDKN1C protein, human; C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004791:Enzyme Inhibitors; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; C496910:Kcnq1 protein, mouse; D009687:Nuclear Proteins; D024642:Potassium Channels, Voltage-Gated