Epigenetic and phenotypic consequences of a truncation disrupting the imprinted domain on distal mouse chromosome 7.
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.
Department of Medical Genetics, Life Sciences Centre, Molecular Epigenetics Group, 5503-2350 Health Sciences Mall, University of British Columbia, Vancouver, British Columbia, Canada.
Rosemary
R
Oh
Rita
R
Ho
Lynn
L
Mar
Marina
M
Gertsenstein
Jana
J
Paderova
John
J
Hsien
Jeremy A
JA
Squire
Michael J
MJ
Higgins
Andras
A
Nagy
Louis
L
Lefebvre
D000483:Alleles; D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics*; D019175:DNA Methylation; D053595:Embryonic Stem Cells; D044127:Epigenesis, Genetic; D018392:Genomic Imprinting; D006579:Heterozygote; D051379:Mice; D010641:Phenotype; D017384:Sequence Deletion