2 - The study of the epigenome the genome-wide pattern of methyl groups and other

epigenetic markers
has led to important insights into differences in gene expression between normal and diseased
cells. For
example, aberrant DNA methylation patterns and histone modifications are found in human
cancer cells
(Disease box 12.1) and in patients with fragile X mental retardation (Disease box 12.2).
Imprinting is reprogrammed or reset in the germline by erasure of the DNA methylation
marks in the
primordial germ cells (Fig. 12.4). This appears to be an active demethylation process involving
yet unknown
enzymatic activities. Imprinted genes subsequently acquire different marks in the sperm and the
egg, and
these methylation marks are heritable through subsequent cell divisions. Methylation is an ideal
marker for
imprinting, since it can be established by de novo methylation in one of the gametes.
3 - However, a small class of genes is monoallelically
expressed, i.e. transcribed preferentially from a single allele in each cell (Table 12.1). In most
cases of
monoallelic gene expression, cells randomly select only one allele to encode RNA and protein
for that gene.
This is typical in cells of the immune system and in olfactory neurons, and is considered to be a
way of
ensuring that a single kind of receptor is displayed on the cell surface. An exception is genomic
imprinting
where selection of the active allele is nonrandom and based on the parent of origin.
Monoallelic expression in mammals is exemplified by genomic imprinting, X chromosome
inactivation,
and allelic exclusion. Epigenetic silencing mechanisms play a role in all three systems. In
addition,
programmed gene rearrangements rearrangements of DNA that regulate the expression of
some genes
play a central role in some forms of allelic exclusion. Classic examples include mating-type
switching in
yeast, antigen switching in trypanosomes, and V(D)J recombination in the mammalian immune
system.
The primary function of eukaryotic DNA methylation may be defense of the genome from the
potentially
detrimental effects of transposable elements. An overview of the types of transposable elements
and the
phenotypic consequences of their movement within the genome is followed by a discussion of
their
epigenetic silencing.
8 - Random X chromosome inactivation in female mammals balances the transcriptional dosage
between
XX females and XY males. In the early embryo there is random inactivation of one X
chromosome. The

inactive X is stably maintained in all progeny of a given cell. This leads to cellular mosaicism in
adult
females. X inactivation is controlled by the X inactivation center. XIST transcript levels are
upregulated
from the chromosome that will become the inactive X, while the overlapping antisense Tsix
transcript is
downregulated. Silencing involves coating of the X chromosome with XIST RNA and a series of
epigenetic
chromatin modifications, including histone methylation and hypoacetylation, and enrichment of
variant
histone macroH2A. About 15% of genes escape inactivation and in an additional 10% the level
of expression
differs from woman to woman.
11 In eukaryotes, three different DNA polymerases are involved in chromosomal DNA
replication: DNA
polymerase , , and

14 -