Biology Reference
In-Depth Information
availability of complementary techniques to study DNA methylation. Details
on the timing and drivers of gametic DNAmethylation are reported in
Chap-
ters 2 and 5
. To summarize, erasure of somatic DNA methylation patterns in
the future gametes occurs in two waves during embryonic life, first during the
migration of the primordial germ cells (PGCs) toward the genital ridges and
secondly at the time of PGC entry into these future gonads (
Guibert, Forne, &
Weber, 2012; Hackett et al., 2012; Popp et al., 2010
). Next, establishment of
DNA methylation profiles is specified separately in the differentiating female
and male germlines under the control of sex-specific signaling pathways and
kinetics (
Schaefer, Ooi, Bestor, & Bourc'his, 2007
). Maternal methylation
patterns are established postnatally during the growing phase of meiotically
arrested oocytes. In contrast, paternal methylation patterns are acquired very
early, during fetal life, and will be propagated until the release of mature
sperm, which require successive cell divisions and can span decades in
long-lived mammalian species such as humans.
As a result of these sex-specific programs, the mature oocyte and sperm
harbor very different genomic methylation patterns. This was shown on a
global level in early studies, where quantification of DNA methylation con-
tent revealed that the oocyte genome is less methylated than the sperm
genome (
Monk, Boubelik, & Lehnert, 1987
). Evidence for gametic differ-
ences in DNA methylation also came from the identification of imprinting
control regions (ICRs), which are
cis
-regulatory elements that control the
expression of imprinted genes and which carry, by definition, parent-specific
DNA methylation marks inherited from the gametes. Around 23 ICRs have
been identified in the mouse, which in turn control the parent-specific
monoallelic expression of some 130 imprinted genes. Maternal ICRs are
specifically methylated in the oocyte but not in sperm, while paternal ICRs
are methylated in sperm but not in the oocyte. The sexual dimorphism of the
ICRs not only arises from exclusive parental methylation but also from
the number of ICRs methylated in each parental gamete: only three ICRs
aremethylated in spermand all the remaining ones aremethylated in the oocyte,
illustrating a strong bias toward the maternal genome in imprinting control
(
Proudhon et al., 2012; Reik &Walter, 2001; Schulz et al., 2010
). Moreover,
whilematernallymethylated ICRs coincide systematicallywithCpG-rich pro-
moters, the three known paternallymethylated ICRs map to intergenic regions
with a relatively poor CpG content.
It was generally assumed that sex-specific DNA methylation was prefer-
entially targeted to these ICRs. However, recent advances in techniques that
permit genome-wide methylation analysis of small quantities of DNA have
