The Questions of Developmental Biology

In vertebrates, the presence of methylated cytosines in the promoter of a gene correlates
with the repression of transcription from that gene. In developing human and chick red blood
cells, the DNA of the globin promoters is almost completely unmethylated, whereas the same
promoters are highly methylated in cells that do not produce globin. Moreover, the methylation
pattern changes during development (Figure 5.20B). The cells that produce hemoglobin in the
human embryo have unmethylated promoters for the genes encoding the -globins of embryonic
hemoglobin. These promoters become methylated in the fetal tissue (van der Ploeg and Flavell
1980; Groudine and Weintraub 1981; Mavilio et al. 1983). Similarly, when the fetal globin gives
way to adult globin, the -globin gene promoters become methylated. The correlation between
methylated cytosines and transcriptional repression has been confirmed experimentally. By
adding transgenes to cells and giving them different patterns of methylation, Busslinger and coworkers
(1983) showed that methylation in the promoter or enhancer of a gene correlates
extremely well with the repression of gene transcription. In vertebrate development, the absence
of DNA methylation correlates well with the tissue-specific expression of many genes.
Possible mechanisms by which methylation represses gene transcription
How is methylation involved in repressing genes? One hypothesis is that methylated
DNA stabilizes nucleosomes. Here, DNA methylation is linked to histone deacetylation. Whereas
acetylated histones are relatively unstable and cause the nucleosomes to disperse (see above),
deacetylated histones form a stable nucleosome. The protein MeCP2 selectively binds to
methylated regions of DNA; it also binds to histone deacetylases. Thus, when MeCP2 binds to
methylated DNA it can stabilize the nucleosomes in that particular region of chromatin (Keshet et
al. 1986; Jones et al. 1998; Nan et al. 1998). Methylated DNA may also be preferentially bound
by histone H1, the histone that associates nucleosomes into higher-order folded complexes
(McArthur and Thomas 1996). These patterns are maintained through cell division by the enzyme
DNA (cytosine-5)-methyltransferase. During replication, one strand of the DNA (the template
strand) retains the methylation pattern, while the newly synthesized strand does not. However, the
enzyme DNA (cytosine-5)-methyltransferase has a strong preference for DNA that has one
methylated strand, and when it sees a methyl-CpG on one side of the DNA, it methylates the new
C on the other side (Gruenbaum et al. 1982; Bestor and Ingram 1983).
Genomic Imprinting
It is usually assumed that the genes one inherits from one's father and the genes one
inherits from one's mother are equivalent. In fact, the basis for Mendelian ratios (and the Punnett
square analyses used to teach them) is that it does not matter whether the genes came from the
sperm or from the egg. But in some cases, it does matter. In certain mutations of mice and
humans, a severe or lethal condition arises if the mutant gene is derived from one parent, but that
same mutant gene has no deleterious effects if inherited from the other parent. For instance, in
mice, the gene for insulin-like growth factor II (Igf-2) on chromosome 7 is active in early
embryos only on the chromosome transmitted from the father. Conversely, the gene (Igf-2r) for a
protein that binds this growth factor, located on chromosome 17, is active only in the
chromosome transmitted from the mother (Barlow et al. 1991; DeChiara et al. 1991; Bartolomei
and Tilghman 1997). The Igf-2r protein acts to bind and degrade excess Igf-2. A mouse pup that
inherits a deletion of the Igf-2r gene from its father is normal, but if the same deletion is inherited
from the mother, the fetus experiences a 30% increase in growth and dies late in gestation.*
In humans, the loss of a particular segment of the long arm of chromosome 15 results in
different phenotypes, depending on whether the loss is in the male- or the female-derived