Biology Reference
In-Depth Information
3.5. Global demethylation in erythropoiesis
Once established in somatic cells, DNA methylation levels were thought to
be very stable. This view has been challenged by the surprising discovery that
mouse erythropoiesis is associated with global DNA demethylation
in vivo
(
Shearstone et al., 2011
). The formation of erythrocytes (enucleated red
cells) first occurs from erythroid progenitors in the murine fetal liver
between E11 and E15 and can be followed by isolating cellular populations
at different stages of maturation with surface markers. Using global measure-
ments by ELISA, the authors observed a striking loss of global CpG meth-
ylation from 70% to 30% during differentiation in the course of around three
cell divisions. Using reduced representation bisulfite sequencing that pro-
vides quantitative mapping of 5mC in a large portion of CpG-rich regions,
the authors confirmed that there is a progressive decrease in methylation
levels from 79% to 55% in the covered regions. Demethylation affects a
broad range of sequences including promoters, enhancers, repeats, and even
imprinted loci, which is not associated with global changes in gene expres-
sion. Further mechanistic studies showed that this demethylation requires
cell division and therefore probably reflects a compromised maintenance
of DNAmethylation during DNA replication (
Shearstone et al., 2011
). This
shows that global variations in DNA methylation not only occur in preim-
plantation embryos and PGCs but also during somatic cell differentiation.
4. ROLE OF CYTOSINE METHYLATION IN GENOME
REGULATION
4.1. Genomic imprinting and X inactivation
Early experiments showing that mammalian gynogenetic and androgenetic
embryos are not viable indicated that the maternal and paternal genomes are
not equivalent (
McGrath & Solter, 1984
). This is attributed to a subset of
genes subjected to genomic imprinting, which are expressed only from
the paternal or maternal allele. To date, more than 100 imprinted genes have
been reported, and these are often organized in small clusters. The imprinted
expression of these genes depends on allele-specific DNA methylation in
CpG-rich regions called ICRs (imprinted control region). These acquire
differential DNA methylation in the gametes and have the unique property
to maintain it in the embryo by escaping demethylation on one allele and
de novo
methylation on the other allele. DNA methylation at ICRs is
established in the gametes by DNMT3A and DNMT3L (
Bourc'his et al.,
