Trends in Biomedical Science
Epigenetics 2
The following slides are taken from:
Genetic Science Learning Center (2011, January 24) Gene
Control. Learn.Genetics. Retrieved October 10, 2011, from
http://learn.genetics.utah.edu/content/epigenetics/control/
GENE CONTROL
Signals from the outside world can work through
the epigenome to change a cell's gene
expression.
Look at the interactive at
http://learn.genetics.utah.edu/content/epigene
tics/control/
This Kind of Control has been shown
in cells.
Researchers at McGill University
engineered a type of cell where green
fluorescent protein (GFP) level
provided a readout of gene activity.
Researchers placed the GFP gene into cells
growing in culture dishes. Then they added
different compounds to the cells. They
compared the amount of GFP that the cells
produced before and after they added the
compounds to see whether they made the
gene more or less active.
A compound called AdoMet, a source of
methyl tags, decreased GFP output.
Valproic acid, an anti-epilepsy drug and
mood stabilizer, increased GFP output. The
researchers analyzed the GFP genes from
these cells and confirmed that the
compounds changed the number of methyl
tags attached to the DNA.
In these cells, GFP production is a readout of
gene activity.
Gene Control and Cancer
Cancer cells have a lower level of methylation (more
active DNA) than healthy cells. Too little methylation
causes:
Activation of genes that promote cell growth.
Chromosome instability: highly active DNA is
more likely to be duplicated, deleted, and moved to
other locations.
Loss of imprinting
Cancer cells can also have genes that have more
methyl (are less active) than normal. The types of
genes that are turned down in cancer cells:
Keep cell growth in check
Repair damaged DNA
Initiate programmed cell death
The following slides are taken from:
Genetic Science Learning Center (2011, January 24) The Epigenome learns
from its experiences. Learn.Genetics. Retrieved October 10, 2011, from
http://learn.genetics.utah.edu/content/epigenetics/epi_learns/
THE EPIGENOME LEARNS FROM ITS
EXPERIENCES
Epigenetic tags act as a kind of cellular memory.
A cell's epigenetic profile -- a collection of tags
that tell genes whether to be on or off -- is the
sum of the signals it has received during its
lifetime.
The Changing Epigenome affects
Gene Expression
As a fertilized egg develops into a
baby, dozens of signals received over
days, weeks, and months cause
changes in gene expression patterns.
Epigenetic tags record the cell's experiences
on the DNA, helping to stabilize gene
expression. Each signal shuts down some
genes and activates others as a cell develops
toward its final fate. Different experiences
cause the epigenetic profiles of each cell type
to grow increasingly different over time. In
the end, hundreds of cell types form, each
with a distinct identity and a specialized
function.
In a differentiated cell, only 10 to 20% of the genes are
active. Different sets of active genes make a skin cell
different from a brain cell.
Environmental signals such as diet and stress can trigger
changes in gene expression. Epigenetic flexibility is also
important for forming new memories.
Cells Listen for Signals
The epigenome changes in response to signals.
Signals come from inside the cell, from
neighboring cells, or from the outside world
(environment).
Early in development, most signals come from
within cells or from neighboring cells. The
mother's nutrition is also important at this stage.
The food she brings into her body forms the
building blocks for shaping the growing fetus
and its developing epigenome. Other types of
signals, such as stress hormones, can also travel
from the mother to fetus.
After birth and as life continues, a wider variety
of environmental factors start to play a role in
shaping the epigenome. Social interactions,
physical activity, diet and other inputs generate
signals that travel from cell to cell throughout
the body. As in early development, signals from
within the body continue to be important for
many processes, including physical growth and
learning. Hormonal signals trigger big changes at
puberty
In old age, cells continue to respond to signals.
Environmental signals trigger changes in the
epigenome, allowing cells to respond
dynamically to the outside world. Internal
signals direct activities that are necessary for
body maintenance, such as replenishing blood
cells and skin, and repairing damaged tissues
and organs. During these processes, just like
during embryonic development, the cell's
experiences are transferred to the epigenome,
where they shut down and activate specific sets
of genes.
Proteins Carry Signals to the DNA
Once a signal reaches a cell, proteins carry
information inside. Proteins pass
information to one another. The specifics
of the proteins involved and how they
work differ, depending on the signal and
the cell type. But the basic idea is common
to all cells.
The information
is finally passed
to a gene
regulatory
protein that
attaches to a
specific
sequence of
letters on the
DNA.
The information
is finally passed
to a gene
regulatory
protein that
attaches to a
specific
sequence of
letters on the
DNA.
(more complex example)
Gene Regulatory Proteins Have Two
Functions
1. SWITCH SPECIFIC GENES ON OR OFF
A gene regulatory protein attaches to a
specific sequence of DNA on one or more
genes. Once there, it acts like a switch,
activating genes or shutting them down.
2. RECRUIT ENZYMES THAT ADD AND REMOVE
EPIGENETIC TAGS
Gene regulatory proteins also recruit enzymes
that add or remove epigenetic tags. Enzymes
add epigenetic tags to the DNA, the histones, or
both.
Epigenetic tags give the cell a way to
"remember" long-term what its genes should be
doing.
Experiences Are Passed to Daughter Cells
As cells grow and divide, cellular machinery
faithfully copies epigenetic tags along with the
DNA. This is especially important during
embryonic development, as past experiences
inform future choices. A cell must first "know"
that it is an eye cell before it can decide whether
to become part of the lens or the cornea. The
epigenome allows cells to remember their past
experiences long after the signals fade away.
Using the original DNA strands as a template, methyl
copying enzymes attach methyl tags to newly replicated
DNA copies. One original DNA strand and one copy will
be passed to each daughter cell.
EPIGENETICS AND INHERITANCE
We used to think that a new embryo's
epigenome was completely erased and
rebuilt from scratch.
But this may not be completely true.
Some epigenetic tags may remain in place
as genetic information passes from
generation to generation, a process called
epigenetic inheritance.
Epigenetic inheritance is an
unconventional finding.
In fact there are currently many
arguments about epigenetics generally.
It goes against the idea that inheritance
happens only through the DNA code that
passes from parent to offspring. It means
that a parent's experiences, in the form of
epigenetic tags, can be passed down to
future generations.
Epigenetic inheritance can explain
some strange patterns of inheritance
geneticists have been puzzling over
for decades.
Overcoming the Reprogramming Barrier
Most complex organisms develop from
specialized reproductive cells (eggs and sperm in
animals). Two reproductive cells meet, then they
grow and divide to form every type of cell in the
adult organism. In order for this process to
occur, the epigenome must be erased through a
process called "reprogramming."
Reprogramming is important because
eggs and sperm develop from
specialized cells with stable gene
expression profiles. Their genetic
information is marked with epigenetic
tags.
Before the new organism can grow
into a healthy embryo, the epigenetic
tags must be erased.
At certain times during development
specialized cellular machinery works on
the genome and erases its epigenetic tags
in order to return the cells to a genetic
“empty page."
But, for some genes, epigenetic tags make
it through this process and pass
unchanged from parent to offspring.
Reprogramming resets the epigenome of the early embryo so
that it can form every type of cell in the body. In order to pass to
the next generation, epigenetic tags must avoid being erased
during reprogramming.
Bypassing Reproductive Cells
Epigenetic marks can pass from
parent to offspring in a way that
completely bypasses egg or sperm,
thus avoiding the epigenetic
reprogramming that happens
during early development.
Most of us were taught that our traits
are in the DNA that passes from
parent to offspring.
New information about epigenetics
may give us a new understanding of
what inheritance is.
Nurturing behavior in rats
Rat pups who receive high or low
nurturing from their mothers develop
epigenetic differences that affect their
response to stress later in life.
When the female pups become
mothers themselves, the ones that
received high quality care become high
nurturing mothers. And the ones that
received low quality care become low
nurturing mothers. The nurturing
behavior itself transmits epigenetic
information onto the pups' DNA,
without passing through egg or sperm.
Some mother rats spend a lot of time
licking, grooming and nursing their
pups. Others seem to ignore their pups.
Highly nurtured rat pups tend to grow
up to be calm adults, while rat pups
who receive little nurturing tend to
grow up to be anxious.
Look at
http://learn.genetics.utah.edu/content/epigenetics/rats/
The difference between a calm and an
anxious rat is not genetic - it's
epigenetic. The nurturing behavior of
a mother rat during the first week of
life shapes her pups' epigenomes.
And the epigenetic pattern that the
mother establishes tends to remain,
even after the pups become adults.
Anxious Behavior Can Be an Advantage
The anxious, guarded behavior of the lownurtured rat is an advantage in an
environment where food is scarce and
danger is high. The low nurtured rat is
more likely to keep a low profile and
respond quickly to stress.
In the same environment, a relaxed rat
might be a little too relaxed. It may be
more likely to be eaten.
High-nurturing mothers raise high-nurturing offspring, and low-nurturing
mothers raise low-nurturing offspring. This is not a genetic pattern. Whether
a pup grows up to be anxious or relaxed depends on the mother that raises it
- not the mother that gives birth to it.
The mother’s behavior may epigenetically
program the child’s DNA.
The epigenetic code gives the genome more
flexibility than the fixed DNA code alone. The
epigenetic code passes certain types of
information to offspring without having to go
through the slow process of natural selection. At
the same time, the epigenetic code is sensitive
to changing environmental conditions such as
availability of food or threat from predators.
The Glucocorticoid Receptor (GR) Helps
Shut Down the Stress Response
When confronted with danger, the body
turns on stress circuitry in the brain. Stress
circuitry activates the adrenaline-driven
Fight or Flight response and causes the
hormone cortisol to be released into the
bloodstream.
Cortisol is important for freeing
stored energy, which helps with both
fighting and fleeing. But too much
cortisol can be a bad thing. High
levels can lead to heart disease,
depression, and increased
susceptibility to infection.
Cortisol also travels to an area of the
brain called the hippocampus, where
it binds to GRs. When enough cortisol
is bound, the hippocampus sends out
signals that turn off the stress circuit,
shutting down both the Fight or Flight
response and cortisol production.
See http://en.wikipedia.org/wiki/File:Hippocampus.gif
Stress signals travel from the
hypothalamus to the pituitary gland and
then to the adrenal glands. The adrenal
glands release the hormone cortisol (and
adrenaline, not shown).
See http://en.wikipedia.org/wiki/File:Hypothalamus.gif
Rats (and people) with higher
levels of GR are better at detecting
cortisol, and they recover from
stress more quickly.
When cells in the hippocampus detect
cortisol, which binds to the GR receptor,
they send a signal to the hypothalamus
that shuts down the stress circuit.
Epigenetic Patterns Are Reversible
You can take a low-nurtured rat, inject
its brain with a drug that removes
methyl groups, and make it act just like
a high-nurtured rat. The GR gene gets
turned on, cells make more GR
protein, and the rat acts more relaxed.
It works in the other direction too. You
can take a relaxed, high-nurtured rat,
inject its brain with methionine and make
it more anxious.
Of course drugs affect many genes, so
they're not an exact substitute for
maternal care.
You can also turn an anxious rat into a
more relaxed rat by making its living
quarters more varied.