Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

MECHANISMS THAT REINFORCE CELL MEMORY IN PLANTS AND ANIMALS
407
CG island
introns
RNA
5′
RNA
5′
exons
dihydrofolate reductase gene
3′
hypoxanthine phosphoribosyl transferase gene
3′
DNA
DNA
Figure 7–46 The CG islands surrounding
the promoter in three mammalian
housekeeping genes. The yellow boxes
show the extent of each island. As for
most genes in mammals, the exons (dark
red) are very short relative to the introns
(light red). (Adapted from A.P. Bird, Trends
Genet. 3:342–347, 1987. With permission
from Elsevier.)
ribosomal protein gene
RNA
5′ 3′
10,000 nucleotide pairs
DNA
is later replaced by C either through DNA repair (see Figure 5–41A) or, passively,
through multiple rounds of DNA replication. Unmethylated CG islands have several
properties that make them particularly suitable for promoters. For example,
some of the same proteins that bind to CG islands and protect them from methylation
recruit histone modifying enzymes that make the islands particularly “promoter
friendly.” As a result, RNA polymerase is often found bound to promoters
within CG islands, even when the associated gene is not being actively transcribed.
At unmethylated CG islands, the balance between polymerase and nucleosome
assembly is thus tipped toward the former. Additional steps are needed to “push”
the bound polymerase into transcribing the adjacent gene, and these are directed
by transcription regulators that bind to cis-regulatory sequences of DNA (often
well upstream from the CG islands). These regulators serve to release the polymerase
with the appropriate elongation factors (see Figure 7–21C and
MBoC6 m7.84/7.47
D).
Genomic Imprinting Is Based on DNA Methylation
Mammalian cells are diploid, containing one set of genes inherited from the father
and one set from the mother. The expression of a small minority of genes depends
on whether they have been inherited from the mother or the father: when the
paternally inherited gene copy is active, the maternally inherited gene copy is
silent, or vice versa. This phenomenon is called genomic imprinting.
Roughly 300 genes are imprinted in humans. Because only one copy of an
imprinted gene is expressed, imprinting can “unmask” mutations that would
normally be covered by the other, functional copy. For example, Angelman syndrome,
a disorder of the nervous system in humans that causes reduced mental
ability and severe speech impairment, results from a gene deletion on one chromosomal
homolog and the silencing, by imprinting, of the intact gene on the
other homolog.
The insulin-like growth factor-2 (Igf 2) gene in the mouse provides a well-studied
example of imprinting. Mice that do not express Igf 2 at all are born half the
size of normal mice. However, only the paternal copy of Igf 2 is transcribed, and
only this gene copy matters for the phenotype. As a result, mice with a mutated
paternally derived Igf 2 gene are stunted, while mice with a mutated maternally
derived Igf 2 gene are normal.
VERTEBRATE ANCESTOR DNA
RNA
methylation of
most CG sequences
in germ line
Figure 7–47 A mechanism to explain both the marked overall deficiency
of CG sequences and their clustering into CG islands in vertebrate
genomes. White lines mark the location of CG dinucleotides in the DNA
sequences, while red circles indicate the presence of a methyl group on the
CG dinucleotide. CG sequences that lie in regulatory sequences of genes
that are transcribed in germ cells are unmethylated and therefore tend to be
retained in evolution. Methylated CG sequences, on the other hand, tend to
be lost through deamination of 5-methyl C to T, unless the CG sequence is
critical for survival.
many millions of years
of evolution
CG island
VERTEBRATE DNA