Differential regulation of imprinting in the murine embryo and placenta by the Dlk1-Dio3 imprinting control region.
Genomic imprinting is an epigenetic mechanism controlling parental-origin-specific gene expression. Perturbing the parental origin of the distal portion of mouse chromosome 12 causes alterations in the dosage of imprinted genes resulting in embryonic lethality and developmental abnormalities of both embryo and placenta. A 1 Mb imprinted domain identified on distal chromosome 12 contains three paternally expressed protein-coding genes and multiple non-coding RNA genes, including snoRNAs and microRNAs, expressed from the maternally inherited chromosome. An intergenic, parental-origin-specific differentially methylated region, the IG-DMR, which is unmethylated on the maternally inherited chromosome, is necessary for the repression of the paternally expressed protein-coding genes and for activation of the maternally expressed non-coding RNAs: its absence causes the maternal chromosome to behave like the paternally inherited one. Here, we characterise the developmental consequences of this epigenotype switch and compare these with phenotypes associated with paternal uniparental disomy of mouse chromosome 12. The results show that the embryonic defects described for uniparental disomy embryos can be attributed to this one cluster of imprinted genes on distal chromosome 12 and that these defects alone, and not the mutant placenta, can cause prenatal lethality. In the placenta, the absence of the IG-DMR has no phenotypic consequence. Loss of repression of the protein-coding genes occurs but the non-coding RNAs are not repressed on the maternally inherited chromosome. This indicates that the mechanism of action of the IG-DMR is different in the embryo and the placenta and suggests that the epigenetic control of imprinting differs in these two lineages.
Lin
Shau-Ping
SP
Department of Physiology, Development and Neuroscience, University of Cambridge, Anatomy Building, Downing Street, Cambridge CB2 3DY, UK.
Coan
Phil
P
da Rocha
Simao Teixeira
ST
Seitz
Herve
H
Cavaille
Jerome
J
Teng
Pi-Wen
PW
Takada
Shuji
S
Ferguson-Smith
Anne C
AC
D000818:Animals; D002135:Calcium-Binding Proteins; D019175:DNA Methylation; D021901:DNA, Intergenic; D004622:Embryo, Mammalian / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007453:Iodide Peroxidase / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009139:Musculoskeletal Abnormalities / Q000196:embryology / Q000235:genetics; D009141:Musculoskeletal System / Q000196:embryology; D010641:Phenotype; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D024182:Uniparental Disomy
D002135:Calcium-Binding Proteins; D021901:DNA, Intergenic; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C117274:iodothyronine deiodinase type III; D007453:Iodide Peroxidase