Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene.
Maintenance of genomic methylation patterns in mammalian somatic cells depends on DNA methyltransferase-1 (Dnmt1). Mouse oocytes and preimplantation embryos lack Dnmt1 but express a variant of this protein called Dnmt1o. We eliminated Dnmt1o by deletion of the oocyte-specific promoter and first exon from the Dnmt1 locus. Homozygous animals were normal, but most heterozygous fetuses of homozygous females died during the last third of gestation. Although genomic methylation patterns were established normally in Dnmt1o-deficient oocytes, embryos derived from such oocytes showed a loss of allele-specific expression and methylation at certain imprinted loci. Transient nuclear localization of Dnmt1o in 8-cell embryos suggests that this variant of Dnmt1 provides maintenance methyltransferase activity specifically at imprinted loci during the fourth embryonic S phase.
Howell
C Y
CY
Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
Bestor
T H
TH
Ding
F
F
Latham
K E
KE
Mertineit
C
C
Trasler
J M
JM
Chaillet
J R
JR
D000818:Animals; D001755:Blastocyst / Q000502:physiology; D002467:Cell Nucleus / Q000201:enzymology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation; D004624:Embryo Transfer; D005314:Embryonic and Fetal Development; D005091:Exons; D005260:Female; D005313:Fetal Death; D014644:Genetic Variation; D018392:Genomic Imprinting; D005865:Gestational Age; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009865:Oocytes / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D017384:Sequence Deletion
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse