Loss of DNMT1o Disrupts Imprinted X Chromosome Inactivation and Accentuates Placental Defects in Females
Figure 7
Model of the dynamic regulation of methylation maintenance by DNMT1o and establishment of imprinted XCI during preimplantation development.
Wild-type XX: Maternally produced DNMT1o translocates into the nucleus of 8-cell embryos. Nuclear DNMT1o produces a ‘boost’ to maintain methylation marks on DMDs, and sequences on the X chromosome, repeats and other specific sequences. In the blastocyst, a reprogramming and de novo methylation phase takes place in the inner cell mass (ICM) [65] and high levels of global genome methylation are observed in this cell lineage. Imprinted XCI is maintained on the Xp in the extraembryonic derivatives, while in the ICM the reprogramming activity reactivates the Xp and random XCI causes inactivation of either the Xm or Xp. Dnmt1omat−/− XY and Dnmt1omat−/− XX: Lack of DNMT1o at the 8-cell stage prevents the methylation ‘boost’ and causes a failure in the maintenance of methylation marks on DMDs and other sequences including repeat sequences and X-linked genes. This failure of maintenance methylation at the 8-cell stage results in expression from both Xp and Xm in the extraembryonic lineage (relaxation of imprinted XCI). Activation of both X chromosomes in extraembryonic tissues is associated with methylation loss at repeat elements as well as other sequences across the genome. In contrast, the reprogramming event in the ICM restores proper epigenetic patterns and normal random XCI is established in XX embryos. Following the reprogramming and de novo methylation phase, the global DNA methylation levels in the XY and XX cells derived from ICM are similar to wild-type.