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Molecular and Cellular Biology, February 2008, p. 1092-1103, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01019-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Epigenetic and Phenotypic Consequences of a Truncation Disrupting the Imprinted Domain on Distal Mouse Chromosome 7{triangledown} ,{dagger}

Rosemary Oh,1 Rita Ho,1 Lynn Mar,2 Marina Gertsenstein,3 Jana Paderova,4 John Hsien,3 Jeremy A. Squire,4,5 Michael J. Higgins,6 Andras Nagy,3 and Louis Lefebvre1*

Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada,1 Dana-Farber Cancer Institute, Boston, Massachusetts 02115,2 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada,3 Applied Molecular Oncology, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario M5G 2M9, Canada,4 Department of Medical Biophysics, University of Toronto, Ontario M5G 2M9, Canada,5 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 142636

Received 10 June 2007/ Returned for modification 28 August 2007/ Accepted 5 November 2007

The distal end of mouse chromosome 7 (Chr 7) contains a large cluster of imprinted genes. In this region two cis-acting imprinting centers, IC1 (H19 DMR) and IC2 (KvDMR1), define proximal and distal subdomains, respectively. To assess the functional independence of IC1 in the context of Chr 7, we developed a recombinase-mediated chromosome truncation strategy in embryonic stem cells and generated a terminal deletion allele, DelTel7, with a breakpoint in between the two subdomains. We obtained germ line transmission of the truncated Chr 7 and viable paternal heterozygotes, confirming the absence of developmentally required paternally expressed genes distal of Ins2. Conversely, maternal transmission of DelTel7 causes a midgestational lethality, consistent with loss of maternally expressed genes in the IC2 subdomain. Expression and DNA methylation analyses on DelTel7 heterozygotes demonstrate the independent imprinting of IC1 in absence of the entire IC2 subdomain. The evolutionarily conserved linkage between the subdomains is therefore not required for IC1 imprinting on Chr 7. Importantly, the developmental phenotype of maternal heterozygotes is rescued fully by a paternally inherited deletion of IC2. Thus, all the imprinted genes located in the region and required for normal development are silenced by an IC2-dependent mechanism on the paternal allele.


* Corresponding author. Mailing address: Department of Medical Genetics, Life Sciences Centre, Molecular Epigenetics Group, 5503-2350 Health Sciences Mall, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3. Phone: (604) 822-5310. Fax: (604) 822-5348. E-mail: louis.lefebvre{at}ubc.ca

{triangledown} Published ahead of print on 26 November 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.


Molecular and Cellular Biology, February 2008, p. 1092-1103, Vol. 28, No. 3
0270-7306/08/$08.00+0     doi:10.1128/MCB.01019-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.







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