1. Trends in Biomedical Science Epigenetics 2

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/

3. 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/ http://learn.genetics.utah.edu/content/epigene tics/control/

4. 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.

5. 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.

6. 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.

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

8. 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

9. 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

10. 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/

11. 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.

14. 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.

15. 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.

16. 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.

17. 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).

18. 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.

19. 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

20. 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.

21. 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.

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

23. (more complex example)

24. 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.

26. 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.

28. 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.

29. 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.

30. 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.

31. 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.

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

33. 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."

34. 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.

35. 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.

36. 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.

37. 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.

38. 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.

39. 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.

40. 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.

41. 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/

42. 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.

43. 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.

45. 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.

46. 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.

47. 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.

48. 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.

49. 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

50. 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

51. Rats (and people) with higher levels of GR are better at detecting cortisol, and they recover from stress more quickly.

52. 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.

53. 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.

54. 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.