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of DNMT3 enzymes or lack of DNA replication (as in oocytes and neu-
rons). It is, however, unknown if this non-CpG methylation plays any func-
tional role. Surprisingly, although initial experiments suggested that
intragenic-methylated CpGs inhibit transcriptional elongation (
Lorincz,
Dickerson, Schmitt, & Groudine, 2004
), gene-body methylation positively
correlates with gene expression (
Ball et al., 2009; Hellman & Chess, 2007;
Kobayashi et al., 2012; Laurent et al., 2010
). One possible explanation is that
intragenic methylation favors elongation by inhibiting transcription from
alternative promoters in gene bodies (
Illingworth et al., 2010; Maunakea
et al., 2010
), but this remains to be further studied.
Recently, a class of low-methylated regions (LMRs) was described in
mouse ES cells. LMRs have on average 30% CpG methylation, are CpG
poor, and correspond to distal regulatory regions such as enhancers, DNase
I hypersensitivity sites, or CTCF-binding sites (
Fig. 2.3
B;
Stadler et al.,
2011
). These sequences undergo demethylation as a consequence of tran-
scription factor binding, which suggests that DNA methylation is not caus-
ally involved in their regulation but could potentiate their activity once
transcription factors are bound (
Serandour et al., 2011; Stadler et al.,
2011
). Similar to enhancers, there is also evidence that high CpG methyl-
ation found at many CpG-poor promoters (
Meissner et al., 2008; Weber
et al., 2007
) does not prevent transcription activation and can be reversed.
For example, demethylation at CpG-poor promoters has been observed fol-
lowing transcriptional activation by hormones (
Kim et al., 2009; Metivier
et al., 2008
), and in muscle (
Lucarelli, Fuso, Strom, & Scarpa, 2001
), liver
(
Nagae et al., 2011; Waterland et al., 2009
), hematopoietic cells (
Calvanese
et al., 2012
), differentiation of monocytes into dendritic cells (
Klug et al.,
2010
), and neurons upon neuronal activation (
Guo, Ma, et al., 2011
), which
does in some but not all genes correlate with gene activation. Interestingly,
some of these examples are nondividing cells, which indicates that demeth-
ylation must be replication independent.
In contrast to the rest of the genome, CpG islands are mostly
unmethylated. This is particularly evident for CpG island promoters of
protein-coding genes that are constitutively unmethylated even when the
associated gene is not expressed (
Meissner et al., 2008; Weber et al.,
2007
), whereas intergenic and intragenic CpG islands are more susceptible
to DNA methylation (
Illingworth et al., 2010; Maunakea et al., 2010
). It is
unclear why CpG islands are refractory to DNA methylation, one possibility
being that it has evolved as a way to ensure that promoters of housekeeping
genes remain in a transcriptionally competent state. There are only few
