Biology Reference
In-Depth Information
investigation. Leading hypotheses, including further oxidation and DNA
repair pathways, can be found in
Chapter 2
and W. Reik's chapter.
The differential treatment of the two parental pronuclei probably arises
through a combination of mechanisms. Notably, H3K9me2 enrichment was
shown to protect the maternal pronucleus from global TET3-induced con-
version to hydroxymethylation via the recruitment of oocyte-provided
STELLA/PGC7 protein (
Fig. 9.1
B), a protein involved in chromatin
condensation and transcriptional repression (
Liu, Nakamura, & Nakano,
2012; Nakamura et al., 2006, 2012; Szabo & Pfeifer, 2012
). On the paternal
pronucleus, lack of H3K9me2, combined with hyperacetylation, may
contribute to enhanced accessibility to TET enzymes. However, remark-
ably, STELLA specifically protects two paternal ICRs from active paternal
DNA demethylation, which allows their propagation beyond the one-cell
stage (
Nakamura et al., 2006
).
A recent stage-by-stage RRBS methylome analysis provided the first
genome-wide sequence resolution map of DNA methylation changes during
this important transition period (
Smith et al., 2012
). In agreement with the
cytological studies, a 10-60% drop was observed between gametic and one-cell
zygotic DNA methylation levels, such that the sequences which are interme-
diately methylated in the zygote correspond to the sequences that are highly
methylated in the oocyte and sequences with nearly no methylation in the
zygote are highly methylated in the sperm. By tracking parent-specific infor-
mation at several loci using single nucleotide polymorphisms, the specific loss
of paternal methylation was demonstrated. As the spermmostly provides DNA
methylation at repeats, the methylation loss was confirmed to occur at specific
families of LINE-1 elements, in particular, the Tf and Gf classes, as well as at
LongTerminal Repeat (LTR) retrotransposons, which resemble infectious ret-
roviruses in their genomic organization and sequences. One notable exception
occurs at the LTR family of IAP elements, which are particularly aggressive in
the mouse genome and exhibit intrinsic resistance to DNA demethylation in
several developmental contexts (
Lane et al., 2003
). As hydroxymethylcytosines
andmethylcytosines are indistinguishable in bisulfite-based assays (
Huang et al.,
2010
), the lack of methylation-associated reads on the paternal pronucleus
implies that complete conversion toward demethylation has already occurred.
This is in agreement with the fact that the one-cell embryo pools used in this
RRBS study were collected 10 hours postfertilization.
The biological significance of such an abrupt and early demethylation of
the paternal genome is unknown. Allowing demethylation of paternal
retrotransposons could pose a danger to the early embryo, as reactivation
