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3.3. A relationship between DNA methylation and
transcriptional repression?
Leaving the aforementionedobservations aside, onemaywonderwhether pro-
motermethylation correlates at all with gene expression in embryos. The over-
all repressive effect of promoter methylation on transcription—this notably
depends onCpGcontent (
Weber et al., 2007
)—has previously suggesteda view
of a DNA methylation-dependent mechanism of pre-ZGA gene silencing
(
Stancheva et al., 2002
). Since DNA methylation loss can lead to the activa-
tion of repressed genes, the postfertilization wave of genome-wide DNA
demethylation may establish a transcriptionally permissive state favoring gene
activation at the time of ZGA (
Stancheva et al., 2002
). Depletion of the main-
tenance DNA methyltransferase Dnmt1 in
Xenopus
leads to gene activation
beforeZGA (
Stancheva&Meehan, 2000
). This only occurs on genes normally
expressed at ZGA, whereas genes scheduled for expression later in develop-
ment are unaffected. A local gene activation event in the context of overall
DNA demethylation would be consistent with a local “prepatterning” of gene
expression by some other mechanism—for example, by histone modifications
(as discussed below), already established on the cohort of genes scheduled for
expression upon ZGA. One might also not exclude an indirect role of DNA
methylation on transcriptional repression before ZGA, notably through Kaiso,
amethylatedCpG-specific repressor important for pre-ZGAgene repression in
Xenopus
and zebrafish (
Ruzov et al., 2004, 2009
). During organogenesis and
terminal differentiation, however, the repressive effect of DNA methylation
seems to be restored (
Bogdanovic et al., 2011; Rai et al., 2006
).
4. DEVELOPMENTAL GENE EXPRESSION
PREPATTERNING BY DNA HYPOMETHYLATION
The hypomethylated state of promoters appears to be more informative
for a patterning of developmental gene expression than the methylated state.
In addition to methylated promoters, nearly 50% of RefSeq promoters are
hypomethylated; that is, they display a methylation level by MeDIP-chip sta-
tistically below genome-average methylation (
Andersen, Reiner, et al., 2012
;
Fig. 3.3
A). Hypomethylated promoters are mostly CpG-rich andmost remain
hypomethylated throughout the MBT period. As for methylation, we find
little correlation between expression and DNA hypomethylation during these
stages. In fact, cohorts of genes differentially expressed during this period show
distinct promoter methylation patterns related to CpG content rather than
expression state (
Andersen, Reiner, et al., 2012
).
