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migration) and undetectable by IF staining at E21 (
Hyldig, Croxall, et al.,
2011
). Furthermore, in PGCs at E17 an increased proportion of cells were
found in G2 of the cell cycle, possibly paralleling the G2 arrest observed in
mice. The early stage of reprogramming has not been studied in other mam-
mals and is particularly difficult to study in humans due to the lack of human
material available at this early stage of development. However, PRMT5 is
coexpressed with BLIMP1 in human gonocytes (
Eckert et al., 2008
)
suggesting some similarities with the mouse, at least in the expression of this
epigenetic regulator.
4.2. Late
Once PGCs have arrived in the genital ridges, a major epigenetic repro-
gramming event ensues at E11. There is genome-wide DNA demeth-
ylation, changes in chromatin structure, and loss of numerous histone
modifications brought about by genome-wide histone replacement
(
Hajkova et al., 2002, 2008
). DNA demethylation in PGCs appears to occur
rapidly, suggesting an active process, and may entail the DNA repair path-
way (
Hajkova et al., 2010
). This reprogramming results in demethylation of
many repetitive elements but critically includes the erasure of imprints
(
Hajkova et al., 2002
), allowing the establishment of sex-specific imprints
during gametogenesis (
Reik, 2001
). The mechanism of DNA demethyla-
tion remains controversial (
Ooi & Bestor, 2008
) and has been extensively
reviewed elsewhere (
Branco, Ficz, & Reik, 2012; Hackett, Zylicz, &
Surani, 2012; Hajkova, 2011; Saitou, Kagiwada, & Kurimoto, 2012;
Wu & Zhang, 2010
).
Very little is known about the process of imprint erasure in other mam-
mals. Themost detailed analysis to date has been in pig embryos (Hyldig et al.,
2011a,b). As observed for mouse embryos, there is a global decrease in meth-
ylation at repetitive sequences occurring on arrival at the genital ridge. This
seems to coincide with demethylation of the
Igf2/H19
and
Igf2r
imprinted
genes. However, in male embryos,
Igf2r
demethylation appears to be occur-
ring during migration, an interesting difference that merits further investiga-
tion. There is an intimate relationship between H3K9me2 and DNA
methylation, and it is possible that low H3K9me2 facilitates DNA demeth-
ylation in PGCs. Mouse PGC development lasts less than a week, but in the
pig it progresses over 2-3weeks and is likely evenmore prolonged in humans.
Thus, in species with longer gestation, it is possible that the unique histone
modification profile established during early reprogrammingmay play amore
