Biology Reference
In-Depth Information
prominent role in facilitating DNA demethylation. Nevertheless, arrival at
the genital ridge is accompanied by a large global decrease in DNA methyl-
ation in pig PGCs, a pattern similar to the mouse.
In humans, very few observations have been reported with regard to
chromatin changes and DNA demethylation in PGCs. Indeed, a definitive
timeline of when these events occur in humans has not been established. As
genome-wide epigenetic reprogramming is completed prior to the onset of
meiosis in mouse female germ cells, it is speculated that reprogramming of
human germ cells, including DNA demethylation and chromatin remo-
deling, should indeed be completed before week 10 (commencement of
meiosis in some female germ cells). However, published observations of epi-
genetic changes in human PGCs have almost exclusively examined later
stage gonocytes, rather than PGCs. An immunohistochemical study of
global 5mC level shows that both female and male human fetal germ cells
are hypomethylated at week 13 postconception, approximately 3 weeks
after the commencement of meiosis in female (
Wermann et al., 2010
). As
transposon-related elements occupy about 40% of the genome while genes
only occupy 2-3% (
Lander & International Human Genome Sequencing
Consortium, 2001; Waterston & Mouse Genome Sequencing
Consortium, 2002
), the low 5mC level detected by immunohistochemical
method suggests that germ cells have already undergone genome-wide
demethylation of retrotransposons by this stage. Indeed, the number of
hypomethylated male fetal germ cells decline from week 13 to the time
of birth, indicating gradual remethylation of the genome after global
DNA demethylation (
Wermann et al., 2010
). Regarding chromatin states,
human male germ cells at around 16-20 weeks postconception demonstrate
absence/low levels of repressive H3K9me2, H3K27me3, and H3K9me3
modifications but high levels of permissive H3K9ac and H2A.Z marks
(
Almstrup et al., 2010; Bartkova et al., 2011
). In contrast, H3K27me3
and H3K9me3 are present in E13.5 mouse PGCs (after reprogramming),
while H3K9ac and H2A.Z are low/absent. The functional significance of
these intriguing discrepancies in chromatin status between mouse and
human germ cells remain to be explored. It will also be critical to study ear-
lier human PGCs to establish a more accurate timeline of reprogramming
(
Fig. 5.2
), for instance, when genome-wide demethylation is initiated and
for how long it lasts. As human PGC development is more protracted than
the mouse, it is likely that this will take place over a longer time frame which
may facilitate dissection of the molecular events during reprogramming.
Due to the differences in gestation between mice and humans, further
