Biology Reference
In-Depth Information
While several protective mechanisms against gDMR demethylation
have been uncovered, the regulation of gDMR protection against DNA
methylation is not fully understood. CGIs are usually methylation free in
mid-gestation embryos and in adult tissues (
Borgel et al., 2010; Weber
et al., 2007
). Because most of the ICRs are CGIs (the 20 maternal ICRs),
the origin of the intrinsic resistance of CGIs to DNA methylation is likely to
be shared by the unmethylated allele of imprinted CGIs. Genome-wide
studies have excluded the mere CpG enrichment as sufficient to predict
unmethylated states (
Straussman et al., 2009
). This observation is further
confirmed by the fact that transient gDMRs and permanent ICRs do not
differ in terms of CpG content, while they have very different fates in the
wake of embryonic
de novo
methylation (
Proudhon et al., 2012
). In contrast,
sequence specificities embedded within CGIs play an important role in the
exclusion of DNA methylation from most CGIs. Methylation-resistant
CGIs harbor significant strand asymmetry in C and G distribution, leading
to the formation of long R-loop structures, which repel DNMT3B (
Ginno,
Lott, Christensen, Korf, & Chedin, 2012
). In direct relevance to the con-
servation of ICRs, R-loop structures were detected at the unmethylated
allele of the human
SNRPN
ICR. In parallel, studies performed with
environment-controlled transgenes have demonstrated that the presence
of DNA binding sites for transcription factors is sufficient
per se
to recapit-
ulate hypomethylated states, at CGIs but also at CpG-poor sequences, with-
out the requirement of active transcription (
Lienert et al., 2011; Stadler et al.,
2011
). Binding of transcription factors may thus have a shielding effect
against DNMTs and be involved in the protection of unmethylated alleles
of both CpG-rich maternal ICRs and CpG-poor paternal ICRs at implan-
tation. As we discussed earlier, active chromatin profiles linked to H3K4
methylation could also play a role in repelling DNMTs during this stage
of development (
Fig. 9.1
D).
A specific survey of transcription factor binding sites at ICRs may pro-
vide important cues toward unraveling the origin of ICR protection at
implantation. Interestingly, the same rule of protection by binding may
apply later in life during tissue formation. A recently identified newmaternal
ICR, associated with the
Cdh15
M-Cadherin gene, revealed the unex-
pected existence of tissue-specific ICRs, arguing against the prevailing view
that ICR parent-specific methylation patterns are permanent and unalter-
able throughout life (
Proudhon et al., 2012
). While being resolved to
biallelic methylation in all investigated somatic tissues, maternal-specific
methylation is specifically conserved at the
Cdh15
ICR in some cell types
