Biology Reference
In-Depth Information
2001; Hata, Okano, Lei, & Li, 2002; Kaneda et al., 2004; Kato et al., 2007
)
and then maintained during early embryogenesis by DNMT1 (
Hirasawa
et al., 2008
). These ICRs sit directly in the promoter of the imprinted gene
or correspond to insulators and promoters of noncoding RNAs that regulate
imprinted expression in
cis
(
Barlow, 2011
). The study of imprinted genes was
pioneering because it helped to propose novel paradigms; in particular, that
DNA methylation is not only repressive but can also stimulate gene expres-
sion by regulating
cis-
acting repressors. Imprinting methylation marks are
then erased in PGCs of the offspring and set back again according to the
sex of the embryo, thereby completing the cycle. The key role of DNA
methylation in genomic imprinting is demonstrated by the fact that
imprinted expression is perturbed in mice lacking DNMT1 or derived from
gametes that failed to establish DNA methylation (
Bourc'his et al., 2001;
Kaneda et al., 2004; Li, Beard, & Jaenisch, 1993
). Genome-wide DNA
methylation profiling is now used to discover more imprinted loci and indi-
cates that only few gametic ICRs remain to be discovered (
Proudhon et al.,
2012; Xie et al., 2012
), although the precise inventory will require the
systematic investigation of many tissues as imprinting can occur in a
tissue-specific manner (
Prickett & Oakey, 2012
). The key questions are
now to elucidate the mechanisms that establish and maintain differential
gametic DNA methylation, which involves multiple factors such as DNA
sequence, histone modifications, and transcription (
Abramowitz &
Bartolomei, 2012; Chotalia et al., 2009; Ciccone et al., 2009; Li et al.,
2008; Nakamura et al., 2012; Quenneville et al., 2011
).
DNA methylation has also been implicated in the inactivation of one X
chromosome in female cells. By making one of the two X chromosomes tran-
scriptionally silent in female cells, this process equalizes X-chromosome gene
dosage between males and females. In mice, X-chromosome inactivation first
occurs on the paternal X chromosome in the female cleavage-stage embryo,
and subsequently in a randommanner after implantation (
Barakat & Gribnau,
2012
). Similar to genomic imprinting, X-chromosome inactivation depends
on a
cis
-acting X-inactivation center that encodes the Xist noncoding RNA,
which coats the inactive X chromosome and initiates a cascade of events that
include exclusion of the transcription machinery, recruitment of chromatin-
modifying complexes, and DNA methylation of promoter-associated CpG
islands (
Barakat & Gribnau, 2012
). The inactive X chromosome also shows
less DNA methylation in gene bodies compared to the active X (
Hellman
& Chess, 2007
), which further reinforces the link between intragenic
DNA methylation and transcription (see
Section 3.1
). Several studies indicate
