Trends in Biomedical Science
2015 Epigenetics – Introduction
“Ghost in Your Genes” http://www.youtube.com/watch?v=D44cu7v9x1w
The transcript of the video can be found at http://www.pbs.org/wgbh/nova/transcripts/3413_genes.html
The following information from: http://learn.genetics.utah.edu/content/epigenetics
IDENTICAL TWINS
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develop from a single zygote, so have the same genome.
removes genetics as a variable
differences between individuals are caused almost solely by environmental factors.
many of these environmentally induced differences are acquired via the epigenome.
Video Twinsmovie http://learn.genetics.utah.edu/content/epigenetics/twins/
Nature and Nurture - Genetics and the Environment
For more than 100 years,
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characteristics in twins compared to try to find more much certain traits are
inherited,
o eg eye color,
which traits are learned from the environment,
o eg language.
Data is collected and compared
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identical (monozygotic) or fraternal (dizygotic) twins
raised together or apart.
find similarities and differences between these twins
determine the degree to which nature and environment play a role in the trait of
interest.
Twin studies have identified some traits that have a strong genetic component, including
reading disabilities like dyslexia. Other traits, like arthritis, are more likely influenced by the
environment.
A greater similarity between identical twins for a particular trait compared to fraternal twins
provides evidence that genetic factors play a role
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Chromosome 3 pairs in each set of twins.
One twin's epigenetic tags are dyed red and
the other twin's tags are dyed green. When
red and green overlap, that region shows
up as yellow.
The 50-year old twins have more epigenetic
tags in different places than do 3-year-old
twins.
Twin Studies Help Link Environment and Complex Traits
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Identical twins
genetically the same
environments become more unique as they age,
a model for studying how environment and genes interact.
important when studying complex behaviors and diseases.
eg, when only one identical twin in a pair gets a disease, researchers look for elements in
the twins' environments that are different. Data is collected and compared for large
numbers of affected twins and coupled with DNA and gene product analysis.
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Help find the exact molecular mechanism of a disease and determine the extent of
environmental influence.
Can lead to the prevention and treatment of complex diseases.
Eg, for twin pairs where schizophrenia occurs, in 50% of cases both identical twins in
a pair develop the disease, while only 10-15% of cases in fraternal twins show this
pattern.
o evidence for a strong genetic component in susceptibility to schizophrenia.
because both identical twins in a pair don't develop the disease 100% of the time
indicates that there are other factors involved.
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Human genome project.
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Found approximately 20,000-25,000 genes in human DNA.
About the same number of genes as fish and mice.
These few genes didn't seem enough to explain human complexity.
The same key genes that make a fruitfly, a worm or a mouse also make a human.
Chimpanzees share 98.9 percent of our genome.
A different example.
Angelman syndrome.
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Children have a jerky movement when they're walking.
These children have no speech; they big problems with learning
uncharacteristically happy.
A key sequence of DNA is deleted from chromosome 15.
The Prader-Willi syndrome.
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children are very floppy at birth,
a big appetite
get very, very large.
The condition is caused by the same deletion in chromosome 15.
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If the chromosome inherited from father, then Prader-Willi syndrome,
if the deletion was inherited from the mother, then Angelman syndrome.
There must have been a tag or an imprint placed on that chromosome, during either egg or
sperm formation in the previous generation, to say whether it is from the mother or father.
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Although the DNA sequence is the same, the different sets of genes were being
silenced.
Something other than genes passed between generations, and could control genes
directly, switch them on or off.
How?
Video Introducing Epigenome http://learn.genetics.utah.edu/content/epigenetics/intro/
Epigenetic effects can:
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change the expression of genes
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be passed from cell to cell, and even from generation to generation
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don’t involve changes in the DNA sequence.
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NUTRITION AND THE EPIGENOME
Diet - easily studied, and understood, environmental factors in epigenetic change.
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The nutrients from food enter metabolic pathways
changed into molecules the body can use.
one pathway is responsible for making methyl groups - important epigenetic tags
that may silence genes.
Nutrients
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folic acid,
B vitamins and
SAM-e (S-Adenosyl methionine)
key components of this methyl-making pathway.
Diets high in these nutrients can quickly change gene expression,
o especially during early development when the epigenome is first being
formed.
Diet During Early Development Can Cause Changes Lasting Into Adulthood
A mother's diet during pregnancy and what the child is fed as an infant can cause critical
changes that stay with them into adulthood.
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deficiency of methyl-donating folate or choline during late fetal or early postnatal
development causes certain regions of the genome to be under-methylated for life.
For adults, a methyl deficient diet still leads to a decrease in DNA methylation, but
the changes seem to be reversible with resumption of a normal diet.
Agouti Mice
Both mice and people have a gene called agouti.
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When a mouse's agouti gene is completely unmethylated it has a yellow coat color,
is obese and easily gets diabetes and cancer.
When the agouti gene is methylated (as it is in normal mice) the coat color is brown
and the mouse has a low disease risk.
Fat yellow mice and skinny brown are genetically identical.
The fat yellow mice look different because of epigenetics.
When researchers fed pregnant yellow mice a methyl-rich diet, most of the resulting
pups were brown and healthy and stayed that way for life.
So an individual's adult health is heavily influenced by early prenatal factors.
health may be determined by what our parents ate.
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If the agouti gene is switched on all the time, it blocks a receptor in the satiation
center of the brain.
The satiation center tells mice and us when we have eaten enough food.
So the yellow animals literally eat themselves into obesity, diabetes and cancer.
Toxins and Supplements
Bisphenol A (BPA) - used to make polycarbonate plastic.
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in many consumer products including water bottles and tin cans.
pregnant yellow agouti mothers were fed BPA, more yellow, unhealthy babies were
born than normal.
BPA during early development had caused decreased methylation of the agouti gene.
BPA-exposed, pregnant yellow mice were fed methyl-rich foods, the offspring were
predominantly brown.
maternal nutrient supplement had counteracted the negative effects of exposure.
Fathers
Historical records of annual harvests from a small Swedish community.
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food availability between the ages of nine and twelve for the paternal grandfather
affected the lifespan of his grandchildren.
shortage of food for the grandfather was associated with extended lifespan of his
grandchildren.
food abundance associated with a greatly shortened lifespan of the grandchildren.
o Early death was the result of either diabetes or heart disease.
Can We have Nutrigenomics?
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As we better understand the connections between diet and the epigenome, the
opportunity arises for clinical applications.
map our gene variations to help us understand our personalized medical needs.
We also might be able to profile a person’s unique epigenome.
Our epigenome may provide information about how to eat better.
methylation patterns may lead to personalized nutrition plans.
New histone modifications are being discovered.
67 new modifications were published in 2011 by Zhao et al (Cell)
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Lysine crotonylation
Lysine proprionylation
Lysine butyrylation
PolyADP ribosylation
Histone 3 Arginine 2 dimethylation
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The following information 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/epigenetics/control/
This Kind of Control has been shown in cells.
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Green fluorescent protein (GFP) level gives a readout of gene activity.
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.
o AdoMet, a source of methyl tags, decreased GFP output.
o Valproic acid, an anti-epilepsy drug and mood stabilizer, increased GFP
output.
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:
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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 may have other genes that have more methyl (are less active) than normal. The
types of genes that are turned down in cancer cells:
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Keep cell growth in check
Repair damaged DNA
Initiate programmed cell death
The following information 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 - 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.
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The Changing Epigenome affects Gene Expression
As a fertilized egg develops into a baby,
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many signals received over 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.
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.
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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.
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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.
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The mother's nutrition is also important at this stage.
The food 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,
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a wider variety of environmental factors begin shaping the epigenome.
Social interactions, physical activity, diet and other inputs generate signals that
travel from cell to cell throughout the body.
signals from within the body continue to be important for many processes, including
physical growth and learning.
Hormonal signals trigger big changes at puberty
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In old age,
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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.
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
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Once a signal reaches a cell, proteins carry information inside.
Proteins pass information to one another.
The proteins involved and how they work differ, depending on the signal and the cell
type.
The information is finally passed to a gene regulatory protein that attaches to a
specific sequence of letters on the DNA.
Gene Regulatory Proteins Have Two Functions
1. SWITCH SPECIFIC GENES ON OR OFF
2. RECRUIT ENZYMES THAT ADD AND REMOVE EPIGENETIC TAGS
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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
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cells grow and divide,
cellular machinery copies many epigenetic tags along with the DNA.
especially important during embryonic development.
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.
eg. using the original DNA strands as a template, methyl copying enzymes attach
methyl tags to newly replicated DNA copies.
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EPIGENETICS AND INHERITANCE
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Some epigenetic tags may remain in place as genetic information passes from
generation to generation, - epigenetic inheritance.
Epigenetic inheritance can explain some strange patterns of inheritance geneticists
have been puzzling over for decades.
Overcoming the Reprogramming Barrier
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Most complex organisms develop from specialized reproductive cells (eggs and
sperm in animals).
Two reproductive cells fuse, then grow and divide to form every type of cell in the
adult organism.
The epigenome must be erased through a process called "reprogramming."
o important because eggs and sperm develop from specialized cells with stable
gene expression profiles. Their genetic information is marked with epigenetic
tags.
o 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.
For some genes, epigenetic tags pass unchanged from parent to offspring.
Bypassing Reproductive Cells
Nurturing behavior in rats
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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/
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The nurturing behavior of a mother rat during the first week of life shapes her pups'
epigenomes.
The epigenetic pattern that the mother establishes tends to remain, even after the pups
become adults.
Anxious Behavior Can Be an Advantage
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anxious, guarded behavior of the low-nurtured rat is an advantage in an
environment where food is scarce and danger is high.
o the low nurtured rat is more likely to keep a low profile and respond quickly
to stress.
o a relaxed rat might be a little too relaxed. It may be more likely to be eaten.
The epigenetic code gives the genome more flexibility than the fixed DNA code alone.
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passes certain types of information to offspring without having to go through the
slow process of natural selection.
sensitive to changing environmental conditions such as availability of food or threat
from predators.
The Glucocorticoid Receptor (GR) Helps Shut Down the Stress Response
Danger - the body turns on stress circuitry in the brain.
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activates the adrenaline-driven Fight or Flight response
causes the hormone cortisol to be released into the bloodstream.
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).
Cortisol
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important for freeing stored energy, which helps with both fighting and fleeing.
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:Hypothalamus.gif
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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
a low-nurtured rat,
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inject its brain with a drug that removes methyl groups,
it acts just like a high-nurtured rat.
the GR gene gets turned on, cells make more GR protein, and the rat acts more
relaxed.
a relaxed, high-nurtured rat,
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inject its brain with methionine
it becomes more anxious.
Drugs affect many genes, - 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.
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