Biology Reference
In-Depth Information
FIGURE 9.1
Comparison of unmethylated (left panel) and methylated (right panel) cytosines. The arrow
in the left panel marks the #5 position. (The carbons and nitrogens are numbered, in this
case, counter-clockwise beginning with the nitrogen on the bottom.)
position (see Figure
9.1
) and the resulting entity is called 5-methyl cytosine. If we
were to compare the DNA of a pair of differentiated cells (e.g., liver cells or skin
cells), we would observe that they had different patterns of methylation. Patterns of
methylation are correlated with patterns of gene expression in an inverse relationship,
in which silent (non-expressed) genes are methylated. In a particular differentiated
cell type, the pattern of methylation is maintained through successive mitoses by the
action of enzymes called maintenance methylases.
In vertebrate animals, methylated cytosines occur in the dinucleotide sequence
CpG
. This dinucleotide is interesting in that its complement on the other strand of
DNA is also
CpG
, and if the
C
on one strand is methylated, the
C
on the other strand
is too. This state of affairs enables the pattern of DNA methylation to be perpetuated
through successive rounds of replication. When a DNA sequence containing methy-
lated
C
in a
CpG
dinucleotide is replicated, the two daughter strands will each have
the
C
on the template strand methylated and the
C
on the new strand unmethylated.
DNA in this state of half-methylation is the substrate for the maintenance methy-
lase, which will methylate the unmethylated
C
on the new strand and thus restore
the methylation pattern of the parent DNA strand. The methylation pattern, and the
pattern of gene expression, will be inherited through subsequent mitoses.
Methylation of
CpG
dinucleotides is required for normal embryonic develop-
ment and patterns of
CpG
methylation must be established following a generalized
demethylation that occurs early in embryonic development [
2
]. The new methylation
patterns are established by
de novo
methylases and appear to contribute to lineage
restriction during development [
3
,
4
]. In other words, when pluripotent stem cells
give rise to tissue-specific stem cells with more limited differentiation potential, the
promoters of a subset of genes which were formerly active in the pluripotent stem
cells become methylated and transcriptionally silent [
5
].
9.1.2
CpG
Islands
Over time, both methylated and unmethylated cytosines may undergo random deam-
ination reactions. The impact of these deamination reactions differs depending upon
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