Trends in Biomedical Science

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Trends in Biomedical Science

• Epigenetics 2

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• 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/

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• 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.u
  tah.edu/content/epigenetics/control/

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• 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.
  

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• 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.

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• 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.

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• In these cells, GFP production is a readout of
  gene activity.

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• 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

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• 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

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• 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/

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• 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.

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• 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.

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• 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.

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• 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.

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• 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).

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• 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.

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• 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

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• 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.

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• 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.

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• The information is finally passed to a gene
  regulatory protein that attaches to a specific
  sequence of letters on the DNA.

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• The information is finally passed to a gene
  regulatory protein that attaches to a specific
  sequence of letters on the DNA.
• (more complex example)

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• Epigenetic inheritance can explain some strange
  patterns of inheritance geneticists have been
  puzzling over for decades.

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• 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."

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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• 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/epi
  genetics/rats/

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• 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.

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• Anxious Behavior Can Be an Advantage
• The anxious, guarded behavior of the low-nurtured
  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.

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• 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.

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• The mothers behavior may epigenetically program
  the childs 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.

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• 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.

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• 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.

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• 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/FileHippocampus.
  gif

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• 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/FileHypothalamus
  .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.

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• 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.

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• 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.

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• 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.

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