Download THE STUDY OF HERITABLE CHANGES IN GENE FUNCTION THAT

epigenetics
THE STUDY OF HERITABLE CHANGES IN GENE FUNCTION THAT OCCUR
WITHOUT A CHANGE IN THE DNA SEQUENCE.
The Dutch Famine
Following D-Day (June 6, 1944), Allied forces
liberated the southern part of Holland but
stall at Arnheim and fail to clear the vital
port of Antwerp.
In September 1944, the Dutch government
in exile called for a rail strike to aid liberation.
The railroads complied.
The Germans retaliated by embargoing all food transport
to the western Netherlands
Food stocks quickly ran out. By February adult rations in
Amsterdam were down to 580 calories per day.
By liberation day (May 1945) 18,000 to 22,000 people
had died of malnutrition.
Lingering Effects of the Famine
Proximal Effects (babies conceived and carried during famine)
Group A
Mother well-fed for first few months, starved
last few months
Babies low birthweight
Group B
Mother starved first few months, well-fed last
few months
Babies normal birthweight.
Lasting effects on first generation:
Babies from Group A
Stayed small through adulthood. Low obesity rates.
Babies from Group B
Higher than normal obesity rates as adults; higher rates of
diabetes, heart disease and schizophrenia.
Transgenerational Effects
Children of daughters of Group A mothers
normal
Children of daughters of Group B mothers
Heavier than normal at birth and
as adults.
An example of Lamarckian
inheritance??
Change without mutation: cellular
differentiation.
Gilbert Fig. 1.1
Each cell has the
same DNA but
different genes are
expressed in mature
cells
Waddington’s Landscape
Hochedlinger K , and Plath K Development 2009;136:509-523
Epigenetics: control of DNA by
chemical modification
Mechanisms of epigenetics
Silencing of genes by methylation
• Methylation is done by several proteins of the DNMT (DNA
Methyltransferase) family.
• Methylation is done on cytosines where they follow
guanines (“CpG islands” in the DNA).
• These islands are most often found upstream of promoter
regions.
Reading the code I: MeCP2

The protein MeCP2 (Methyl CpG Binding Protein 2) binds to areas of
methylation and catalyzes the formation of a set of proteins which
in turn blocks the transcription of downstream genes. Thus it “reads”
the methylation code.

The gene for MeCP2 is found on the X chromosome. In males, a
deficient MeCP2 gene is lethal. In girls it leads to the development
of Rett syndrome, which primarily affects brain development.
Severity probably depends upon which X chromosome is
inactivated.

This latter fact implies that there may be preferential inactivation of
the maternal chromosome in some organs.
Acetylation of histones regulates mRNA transcription
The acetyl group
• Acetylation uncoils the DNA
allowing for transcription.
• Deacetylation causes the DNA to
coil, suppressing transcription.
(HAT = Histone Acetyltransferase; HDAC = Histone deacetylase)
Imprinting, reprogramming and
differentiation
EPIGENETICS AND REPRODUCTION
Imprinting: origin-specific labelling
by epigenetics
There’s something peculiar about egg
and sperm pronulei.
The fertilized egg must have one of
each, even though two male or two
female pronuclei would provide the
same number of chromosomes
(diploid).
The answer: imprinting

Certain chromosomes are differently methylated in the male
or female gamete.

This methylation identifies the origin of the chromosome in all
cells.

For example, the region on chromosome 15 that has the gene
UBE3A (Ubiquitin-protein ligase, used to label proteins for
destruction by proteasomes).

If this region is methylated (inactive) or missing in the maternal
chromosome the person develops Angleman Syndrome
(developmental delay, absent speech, hypotonia, etc.); if in
the paternal chromosome the person develops Prader-Willi
Syndrome (low birth weight, obesity, mental retardation, etc.)

The implication is that in different parts of the body either but
not both copies of chromosome 15 are expressed.
(There are about 80 imprinted genes in humans. Most are devoted to regulation of fetal development.)
Gamete Reprogramming I

Early in development: gamete progenitor cells migrate to primordial
gonads. At this point they are stripped of nearly all epigenetic markers,
making them totipotent.

As the gamete progenitors differentiate (spermatogenesis/oögenesis),
epigenetic markers appear:

Some are due to specialization of the cells into eggs and sperm

Some are parent-specific, which will later identify the chromosome’s
origin.
 Histones in sperm are replaced by protamines. This allows sperm DNA to
be more highly condensed.
 Prior to fertilization, both egg and sperm DNA is transcriptionally silent.
Gamete Reprogramming II


At fertilization:

sperm protamines are removed and replaced by histones
from the egg. Sperm DNA decondenses and all nonimprinted
methylation is removed.

The oöcyte genome is demethylated more slowly. Again,
imprinted regions are protected.
At implantation:


De novo methylation occurs genome-wide in a lineagespecific pattern. However at this time the fertilized egg is still
totipotent.
During development, epigenetic markers are used to
differentiate cells. Cells move down the Waddington
landscape from totipotent to pluripotent to mature.
Time Scale of Reprogramming
Induced Pluripotent Cells
Imprinting and the battle of the sexes
(sperm is cheap/eggs are expensive)

Male: To ensure passage of my genes to the future I should mate with as many
females as possible and have my offspring as large and robust as possible.

Female: To ensure passage of my genes to the future I should bear robust
offspring but not as such a cost to me as to impair my future ability to bear more
offspring.
Experiment: produce mouse zygote with either
two female chromosome 11 or two male
chromosome 11.
Cattanach and Kirk (1985) Chromosome-11 Parental Source
Effect upon Fetal Growth in Mice. Nature 311 496-498
NB: imprinting of individual genes is
found only in eu- and metatherian
mammals (and flowering plants).
Battle of the Sexes: Igf2 and Igf2r

Igf2 is a gene that codes for Insulin Growth Factor, an substance that enhances
growth in the fetus.

Igf2r is a gene that codes for a protein which “mops up” IGF and prevents its
growth-promoting action.

Both genes are imprinted, but with a difference:


On the chromosome that came from the mother, Igf2 is methylated but Igf2r is not.

On the chromosome that came from the father, Igf2r is methylated but Igf2 is not.
Thus the paternal gene would promote fetal growth while the maternal one
would not. Normally this is a stalemate, but errors in epigenetic marking in either
gamete will alter the balance.
Battle of the Sexes: Fetus vs.
Placenta


In mice , one can remove the nucleus of the egg and then fertilize it with
two sperm pronuclei or two egg nuclei and then implant it.* No fetus will
develop to term, but results are revealing:

Two sperm pronuclei: retarded embryo growth, but placental tissues grew.

Two egg pronuclei: better embryo growth, but diminished placental
development.

Implant mix of the two hybrids: all cells in placenta are ♂♂. All embryo cells ♀♀.
In humans, a situation called “molar pregnancy” results in the
development of a hydatiform mole, a kind of placenta with no fetus. This
has been shown to result from fertilization by one or two sperm of an egg
which has lost its DNA (if one sperm, DNA doubles).
*Surani, Barton and Norris (1987) Influence of Parental Chromosomes on Spatial Specificity in Androgenic [--]
Parthenogenetic Chimeras in the Mouse. Nature 326, 395-397
Battle of the Sexes: Counting
chromosomes.
While both ♂♂ eggs fail, the one with the ♂ X
chromosome survives longer.
The implication is that you need one X from the
mother, not just two Xs.
Somehow the cell is counting X chromosomes so
that females inactivate one of their two Xs but
males (XY) don’t inactivate their sole X
chromosome.
Counting actually results from the physical
contact of two X chromosomes, after which the
Xist center is activated in one of them. Xist is
inactivated epigenetically in the male’s X.