section 26.4
Mechanisms of Gene Regulation in Eukaryotes
605
M é th y la tio n
R e p lic a tio n
r e c o g n iz e d
R e c o g n iz e d
CH
U n m e th y la te d
M éth y latio n
TCGAATCGA
D a u g h te r m o le c u le s
D a u g h te r m o le c u le s
lack in g m eth y l
w ith m é th y la tio n
g r o u p s o n n ew ly
p a tte rn o f
s y n th e s iz e d s tr a n d s
p a re n ta l m o le c u le s
F I G U R E 2 6 -9
Mechanism by which the pattern of methylation in parental DNA is inherited in daughter molecules. The rule is that a C
in a CpG sequence can be methylated only if the C in the complementary CpG sequence is already methylated. For
clarity only, methyl groups have been drawn outside the sugar-phosphate strands.
replication. This requires methylation of a sequence com-
plementary (rather than identical) to a methylated site. A
property of certain DNA methylases shows how a methy-
lated parental strand can direct methylation of the appro-
priate daughter sequence, i.e., these enzymes only methy-
late CpG (embedded in certain surrounding sequences)
and only when the CpG in the opposite strand is already
methylated (Figure 26-9). In this way, the methylation pat-
tern of parental DNA strands is inherited by the daughter
strands.
The sex chromosome composition of human males
and females is XY and XX, respectively. If cells con-
tain more than one X chromosome, all except one are
inactivated. The cells of XX females contain a structure
called a
Barr body,
which is a condensed, heterochro-
matic, transcriptionally inactive X chromosome. The cells
of XXY males also contain a Barr body. XXY males suf-
fer from
Klinefelter’s syndrome;
they are usually men-
tally retarded, sterile, and suffer from physiological and
developmental abnormalities. It is thought that extra X
chromosomes must be prevented from gene expression to
preserve the correct gene dosage in both males and fe-
males.
Evidence for inactivation of one X chromosome in XX
females comes from the observation that females are mo-
saic for X-linked alleles that are heterozygous. For exam-
ple, a woman who is heterozygous for a gene that controls
production of sweat glands has patches of skin that per-
spire and patches that do not. Cells in the patches of skin
that do not perspire express the mutant allele, and the wild
type is silent in the inactive X chromosome. Cells in the
patches of skin that do perspire express the wild type allele,
and the mutant allele is silent. X chromosome inactivation
occurs early in embryonic female development and the
X chromosome that is inactivated is selected at random.
Once selected, the same X chromosome is inactivated in
subsequent cell divisions, which explains why patches of
skin and other tissues differ in the expression of X-linked
heterozygous genetic loci.
Inactivation o f the X chromosome
is thought to occur
in three phases: initiation, spreading, and maintenance.
Initiation involves the choice of chromosome to be inac-
tivated and depends on a unique genetic locus on the X
chromosome called the X-inactivation center
(Xic).
Once
one X-inactivation center has been triggered in a cell, the
other X chromosome is protected from inactivation by a
“blocking signal.” The inactivation signal spreads from
the
Xic
locus, eventually to inactivating almost all of the
genes on that X chromosome. However, at least 19 genes
on inactive X chromosomes have been shown to have some
transcriptional activity, so inactivation is not complete.
Specific maintenance mechanisms ensure that the in-
active X chromosome is clonally transmitted and that it
remains inactive in subsequent cell divisions. Methylation
of CpG islands at the beginning of genes in the inactive
X chromosome appears to play an important role in sup-
pressing gene expression; the corresponding CpG islands
in the active X chromosome are usually unmethylated.
