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However, additional, de novo parental asymmetry is known to arise in the
postimplantation embryo, shaping the somatic or secondary DMRs (som-
DMRs), under the indirect control of gDMRs. As differentiation and expres-
sion programs are established, persisting ICRs and somDMRs accumulate
differential posttranslational histone modifications on the two parental alleles.
However, even the seemingly permanent state of the ICR can be lost, and this
is known to occur in a tissue- and cell type-specific way.
5.1. Reduction of germline DMRs
During preimplantation, active and passive mechanisms of demethylation
are the main forces that reduce the number of parent-specific gDMRs.
The parental allele that is inherited in a methylated state is the one at risk
during this period. Among the 100 gDMRs that were protected until this
stage, very few will proceed through the early postimplantation stages. Dur-
ing this period, the main leveling force is the massive de novo methylation
accompanying pluripotency loss and embryonic differentiation. To allow
further conservation of gDMRs, this time protective mechanisms must be
deployed on the parental allele that is inherited in an unmethylated state.
Embryonic de novo DNA methylation has been shown to be mostly
DNMT3B dependent, although some loci also require the alternative
de novo DNA methyltransferase, DNMT3A ( Borgel et al., 2010; Okano,
Bell, Haber, & Li, 1999 ). This process is initiated around E4.5 and
completed by E9.5 ( Borgel et al., 2010 ). On a genome-wide scale, RRBS
analysis revealed a transition from 20% global methylation in the inner cell
mass at E3.5 to almost 60% in the E7.5 embryo, which is in range with final
somatic genomic methylation levels ( Smith et al., 2012 ). According to this
study, sperm-derived gDMRs disappear by DNA methylation gain on the
formerly unmethylated allele, while most oocyte-derived gDMRs are
resolved to unmethylated states in adult tissues. However, numerous cases
of oocyte gDMRs were clearly demonstrated to be lost by methylation gain
on the formerly unmethylated paternal allele in early postimplantation
development, so that these so-called transient gDMRs exhibit fully meth-
ylated patterns for the rest of life, with no sign of prior imprinted status
( Borgel et al., 2010; Proudhon et al., 2012 ). The function of these
preimplantation-specific gDMRs is of great interest, as they could very
transiently regulate monoallelism and levels of expression of transcripts
during a critical window of embryonic development, in relationship with
pluripotency acquisition and early lineage specification.
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