Download Epigenetics

Epigenetic phenomena
• Epigenetics refers to genetic inheritance
that is not coded by the DNA sequence
• It includes changes in gene expression due
to modification of DNA or change in its
chromatin state (facultative
heterochromatin)
• Lecture will illustrate this with various
examples
X chromosome inactivation
• In female mammals with 2 X chromosomes,
one X is inactivated, i.e. all its genes are
switched off, and it forms the Barr body
• This is to prevent a double dose of Xchromosome gene products relative to that
in male cells
• Which of the 2 X chromosomes is inactive
in a cell line, is usually randomly
determined early in development
The calico cat
• The calico cat is an example of
X-chromosome inactivation
• She is heterozygous for a gene on
the X, one allele gives orange fur,
the other black
• Random X-inactivation in cells
early in development gives
patches with either the orange or
black allele active
• White patches are due to an
autosomal gene, “spotting”
Consequences of X inactivation:
the calico cat
Muscular dystrophy in girls
• Duchenne muscular dystrophy (DMD) is an X-linked
recessive disease, usually only affects boys
• The karyotype of girls with DMD sometimes shows an
X:autosome translocation
• In this case, X-inactivation is not random - the normal X
is always inactivated, because the translocation interferes
with the inactivation process
• Therefore, the normal DMD gene is switched off, and the
other one is disrupted by the translocation
• So these girls show the symptoms of DMD
Genomic imprinting
• Usually it does not make any difference from which parent you got a
particular gene
• But with some genes it does matter - this is called genomic (or genetic)
imprinting
• Example:
– Prader-Willi syndrome (PWS): small stature, obesity, learning
difficulties
– Angelman syndrome (AS): epilepsy, learning difficulties, unsteady gait,
“happy” appearance
– PWS often caused by deletion of a gene “SNRPN” on paternal
chromosome 15
– AS often caused by deletion of the same gene, but the maternallyderived one
– Therefore the gene must be expressed differently depending on which
parent it came from
Father’s imprint on his daughter’s thinking?
• Why are boys more likely to have autism (and other
disorders of social function) than girls?
• Turner’s syndrome (45XO) girls are of normal intelligence
but often have social function problems
• Their single X can be either maternal or paternal in origin
• The ones with a maternal X are much more likely to have
the social problems
• All boys have a maternally-derived X
• So, there could be imprinted gene(s) on the X, which are
involved in social function
• When maternally inherited this could might contribute to
disorders such as autism
Mechanism of imprinting
• The mechanisms of X-inactivation
and imprinting are not fully
understood but both involve DNA
methylation
• DNA can be reversibly methylated
on C bases - fig 11.22 in Hartl
• Methylation of a gene’s promoter
tends to switch it off, due to
binding of a specific protein to
methylated DNA
Determination of methylation
m
CCGG
GGCC
CCGG
GGCC
m
m
CCGG
GGCC
m
Gel electrophoresis of fragments
MspI
HpaII
5
4
3
2
1
Methylated
sites which
are not present
in HpaII digest
Non-methylated site
1
Is methylation state related to gene
activity?
• Many sites within a genes are methylated
• some sites only in certain tissues
• others in all tissues
• A minority of sites are methylated in tissues in which the
gene is not expressed, but are unmethylated in tissues in
which the gene is active
• Experiments suggest that these sites are important
regulators of gene activity
Position-effect variegation (PEV)
• State of chromatin (euchromatin, heterochromatin)
can affect gene expression
• A gene could be moved to a heterochromatic
region by an inversion
• Heterochromatin’s structure tends to switch off
gene expression
An example of PEV
• A mutant allele of the w gene in Drosophila causes
eyes to be white (wild-type is red)
• An inversion of part of the X chromosome causes
eyes to have red and white patches (fig 7.36 in
Hartl)
• This is because of PEV switching off w gene in
some cell lines in the eye
• The boundary between heterochromatin and
euchromatin is not exactly the same in all cell
lines, hence eyes are mosaic
Summary - epigenetic gene regulation
•Both mammalian X inactivation and Drosophila position effect variegation are
examples of epigenetic gene regulation.
•The repressed state caused by the chromatin rearrangement is heritable, but
importantly the decision to induce the repressed state is not encoded by the
genome.