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Abstract
The maintenance of key germline derived DNA methylation patterns during preimplantation development depends on stores of DNA cytosine methyltransferase-1o (DNMT1o) provided by the oocyte. Dnmt1omat−/− mouse embryos born to Dnmt1Δ1o/Δ1o female mice lack DNMT1o protein and have disrupted genomic imprinting and associated phenotypic abnormalities. Here, we describe additional female-specific morphological abnormalities and DNA hypomethylation defects outside imprinted loci, restricted to extraembryonic tissue. Compared to male offspring, the placentae of female offspring of Dnmt1Δ1o/Δ1o mothers displayed a higher incidence of genic and intergenic hypomethylation and more frequent and extreme placental dysmorphology. The majority of the affected loci were concentrated on the X chromosome and associated with aberrant biallelic expression, indicating that imprinted X-inactivation was perturbed. Hypomethylation of a key regulatory region of Xite within the X-inactivation center was present in female blastocysts shortly after the absence of methylation maintenance by DNMT1o at the 8-cell stage. The female preponderance of placental DNA hypomethylation associated with maternal DNMT1o deficiency provides evidence of additional roles beyond the maintenance of genomic imprints for DNA methylation events in the preimplantation embryo, including a role in imprinted X chromosome inactivation.
Highlights
Genomic methylation patterns are initially differentially acquired during male and female gametogenesis by the action of the DNMT3a cytosine methyltransferase and its accessory protein DNMT3L [1,2,3]
We found that a region important for the regulation of the X chromosome inactivation process was hypomethylated in female blastocysts and was associated with sex-specific abnormalities in the placenta, relaxation of imprinted X chromosome inactivation, and disruption of DNA methylation later in development
To confirm whether female placentae, versus male placentae, were more severely affected as a result of maternal DNA cytosine methyltransferase-1o (DNMT1o) deficiency, we examined the morphology of extraembryonic tissues of 9.5dpc conceptuses conceived by crossing wild-type males to wild-type Dnmt1+/+, heterozygous Dnmt1D1o/+ and homozygous Dnmt1D1o/D1o females
Summary
Genomic methylation patterns are initially differentially acquired during male and female gametogenesis by the action of the DNMT3a cytosine methyltransferase and its accessory protein DNMT3L [1,2,3]. Germline derived DNA methylation patterns are subsequently extensively reprogrammed during preimplantation development, and while methylation is lost at many sites across the genome, it is maintained on imprinted genes [4]. DNMT1s, the full length Mr 190,000 form of DNMT1, is expressed at all cleavage stages of preimplantation development, and appears to maintain DNA methylation at all stages except the 8-cell stage [5,6,7,8]. The resulting preimplantation embryos fail to maintain methylation patterns at the differentially methylated domains (DMDs) of imprinted loci [12]. Embryonic methylation at loci other than imprinted genes, including repeat sequences, was unaffected by the DNMT1o deficiency
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