Thursday, February 21, 2013

Mind-blower: epigenetics makes memories

Do you remember your five-year-old birthday party? How about your wedding? Emerging science argues that you can do so because those experiences turned off genes at the time in a certain set of nerve cells in your brain. Stranger still, nerve cells may have this capability because they have re-purposed epigenetic mechanisms that other human cells use to "remember who they are."

To back up for a moment, epigenetic mechanisms are chemical changes that turn genes on and off without changing the genes encoded in DNA that we inherit from our parents. Research in recent years has established that they lend an extra layer of regulatory finesse to human genetics and make our complexity possible.

Epigenetics first made a splash in developmental biology. Researchers realized that while we have the same set of genes in every one of our cells, we develop 250 different cell types by the time we are born. Epigenetic mechanisms switch off a different set of genes (and leave a certain set on) in each cell type to result in the 250 types.

Stem cells that become bone or blood or liver cells as we develop "remember" their specialized nature, and they pass that memory on to their descendants as they divide and multiply in the constant turnover under way in most human organs.

This genetic memory is known to be accomplished by epigenetic mechanisms like methylation, the chemical attachment of a methyl group (one carbon and three hydrogens) to certain spots on the DNA chain. The process can turn surrounding genes off (prevent gene expression), while demethylation can turn them back on in an ongoing back and forth.

It really gets fascinating when you consider that the nerve cells making up the brain, unlike nearly every other human cell type, never divide and multiply, and so they never pass on genetic memory. One theory on this is that nerve cells have put their genetic memory mechanisms to another purpose: remembering.

Most of this is theoretical of course, and it is the subject of intense study in the lab of David Sweatt, Ph.D., chair of the UAB Department of Neurobiology and director of the Evelyn F. McKnight Brain Institute here. He sat down with The Mix to discuss his presentation at a recent UAB Epigenetics Symposium about how nerve cells may have evolved to store memories.

Show notes for the podcast:

1:47 Sweatt's lab explores the role of epigenetics in the adult human brain. That has required a re-definition of epigenetics, a science once thought pertinent only to cells that divide and multiply, and that pass on epigenetic marks to their descendants. Nerve cells in the brain do not divide, multiply or turn over as a population, and yet, epigenetics mechanisms are at work. The field now recognizes that such mechanisms contribute to learning and memory.

4:14 The genetics and epigenetics of inheritance has finally answered one of the most long-standing questions in human history: how are traits passed down from parents to children? Epigenetics in neurobiology is also answering another longstanding, philosophical question: What makes us who we are? It turns out that epigenetic mechanisms "sit at the interface" of nature (genes) and nurture (environmental factors make epigenetic mechanisms that turn genes on and off).

5:58 Epigenetics have provided for scientists a fundamental answer for how a single transient experience can make a permanent change in the biochemistry of the brain. It is no small thing that we are now beginning to understand this once-mysterious process.

8:10 Methylation is the mechanism that silences perhaps half or three-quarters of the genes in the human genome to make a nerve cell a nerve cell. Those changes are life-long, and so that set of silenced genes is the same in that family of cells for a lifetime.

12:02 A foundational discovery made in other labs in recent years is that epigenetic changes to nerve cells are necessary for humans to remember things for the long term. Once the field knew that, they could begin to try to understand the mechanisms.

12:35 If anyone who is listening to this podcast today remembers it tomorrow,  it will be because of changes in the genes being expressed in the nerve cells of their brains as they listen. There is a continuous, dynamic interplay between our experiences and the parts of our genes recording memories. Epigenetic mechanisms are powerful regulators of gene transcription and translation, and appear to have been applied by evolution to the problem of storing memories.

13:22 If evolving nerve cells could talk, they might have said, "OK, I have to control which genes are turned on and off in certain nerve cells to store memories, what is the toolbox I have at hand to accomplish this?" It's the same toolbox of epigenetic mechanisms it uses to control gene expression in general.

13:35 Methylation has been been mentioned as part of the toolbox. Then there is histone acetylation. DNA does not just float around in the nuclei of human cells, but is instead wrapped around protein "spools" called histones that help to organize, protect and regulate them as part of a larger package called chromatin. Part of DNA regulation is spatial, and works by controlling when certain parts of DNA chains are able to unravel from their spools. The unraveling makes a stretch of code accessible to the protein-making machinery. Attachment of an acetyl group (a methyl group plus an oxygen) to a histone tends to make genes on that spool more accessible. In addition, there is phosphorylation and ubiquitination, processes that now appear to regulate both chromatin in general and behavioral memory formation.

14:51 With environmental factors (sunlight, smoking and pollution) known to make epigenetic changes, many labs are trying to determine whether such changes have roles in many diseases. Humans have a protective compartment surrounding their brains that screens out many toxins called the blood-brain barrier.

16:23 Sweatt's presentation at the UAB epigenetics symposium discussed how he is working to determine the exact biochemical mechanisms by which methylation is changing the firing patterns of nerve cells to endow networks of nerves with the ability to store memories. What are the exact and ongoing patterns of active methylation and demethylation as the brain reacts to sensory experiences?

18:00 To study the process of memory formation, Sweatt's lab examines certain classes of basic memories that we share, presumably, with study animals like mice. For instance, to survive, our animal ancestors would have had to be able to remember which places were dangerous and which offered food or security (spatial recognition of surroundings).

19:02 Humans appear to have "place cells" in our hippocampus, the part of the brain that tells you where you are and where you have been. When you walk into a new room, or even a new place in a room, a particular set of hippocampal neurons fires in certain patterns in such a way that allows the brain to record a 3D map of that place. Different cells fire when you are in different places. One experiment under way in Sweatt's lab is seeking to test whether certain DNA methylation patterns enable those cells to record that sense of place.

21:27 All this research is ultimately aimed at understanding the normal brain so as to come up with new treatments for those with disorders that affect memory (dementia, Alzheimer's, etc.) and learning. Sweatt's lab and many others are seek to build the framework for the development of new molecular targets for new kinds of drugs.

The previous three podcasts in this epigenetic series were Epigenetics has impact on health beyond DNA, Epigenetics, aging and cancer and Obesity, exercise and epigenetics: no excuses.

Dr. Sweatt’s research is largely funded by the McKnight Brain Research Foundation.

Thursday, February 14, 2013

Obesity, exercise and epigenetics: no excuses

No excuses. It's the mantra of many a fitness boot camp and weight room. But what if your genes make you more likely to store fat on your body or less likely to lose weight when you exercise?

In the experience of Molly Bray, Ph.D., professor of epidemiology and genetics at UAB, the many obese people she has worked with do not see genetic barriers to weight loss as excuses. To the contrary, learning that their genes are making it harder to lose weight is empowering. New enthusiasm and harder workouts replace the frustration of doing everything your doctor tells you and getting nowhere.

Along with counseling people about genetic components of obesity risk, Bray leads a research effort to understand the mechanisms behind them. As she explained in her presentation at a recent UAB Epigenetics Symposium, some people have versions of genes that contribute to obesity. Risk may be influenced further by epigenetic chemical reactions that determine when genes that control energy use are turned on or off.

To recap for this third podcast in our epigenetics series, the human genetic system is composed of more than genes, the long stretches of DNA that encode instructions for the building of proteins. Proteins are the workhorse molecules that comprise the body's structures and carry its signals. We inherit genes and proteins from our parents largely unchanged, because changes often cause disease or death, even though they are necessary if we are to evolve.

While genes form the basic instructions for human life, they are not very good at changing quickly as our surroundings change. In fact, you and many like you may have to die (say during a plague) before the gene pool gets around to favoring those who happen to have the mutations (slow, random changes in genes) that make some better adapted to survive.

That may explain why we have epigenetic mechanisms: quick, reversible chemical reactions that turn genes on and off, often in response to environmental cues. Research has revealed that many genes are turned on and off epigenetically based on whether or not we eat good food, breathe clean air and exercise, and these changes have consequences for our risk of developing many diseases, including obesity.

Show notes for the podcast:

1:50 Epigenetic changes proceed very rapidly, some believe within 24 hours, said Bray.

2:23 The Human Genome Project, for all it has revealed about the DNA sequence of our genes, could not account for the variation in risk for many diseases going from person to person. Differences in the mechanisms that regulate genes may explain more about this disease risk variability than differences in genes themselves.

3:29 Methylation, the attachment of a methyl group (one carbon plus three hydrogens) to certain spots in the DNA chain, is recognized as a major epigenetic mechanism. It enables other proteins to assemble there in a way that silences or turns off the surrounding gene. Researchers once thought that such methylation marks were made in the womb and persisted throughout life, an idea which gave rise to theories about the fetal origins of adult disease. Then came the discovery of enzymes called demethylases, which remove methyl groups. The field now understands that methylation is an active process, with epigenetic changes occurring throughout life, some of them in response to our diet and excercise patterns.

4:18 One reason that epigenetic changes may be important for each person's obesity risk has to do with a gene called FTO (fat mass and obesity related transcript), said Bray.  Certain versions of this gene are more closely associated with obesity risk than any other gene, with the effect consistently shown in several studies across multiple populations and in people of all ages.

4:55 Researchers theorize that the protein built according to the instructions encoded in the FTO gene may act as a demethylase. Its not known why FTO continues to be associated with obesity, but it could be that an FTO demethylase is turning on or off genes that govern energy balance (e.g. how we burn calories in response to exercise).

5:40 Importantly, regular exercise largely erases the increased risk for obesity associated with the versions of the FTO gene. No one then is doomed by their genes, said Bray, because behavior can change them. A recent, small study showed that a single exercise session changes the methylation status of many genes.

7:24 Bray's lab is currently studying how people respond to exercise. Lack of response to an exercise program can be extremely frustrating, but the answer may be straightforward: work out harder.  Her data shows that clinicians can safely increase exercise intensity for many of these patients, and that current treatment guidelines in this regard may need to change.  People can tolerate harder workouts if that's what it takes, said Bray.

8:06 Genes may influence several aspects of a person's response to exercise, including the tough combination of making you need higher intensity workouts to get results and less able to tolerate them. Exercise for some may not "feel good."

8:22 Generally when people find out that a genetic or epigenetic variation may be affecting their response to exercise, they don't see it as an excuse. They benefit greatly from the insight, and realize they're not "just lazy," Bray said.

9:55 Obesity is associated with inflammation, the out-of-place triggering of the immune response.  Inflammation has been established as one link between obesity and several complex diseases, including cardiovascular disease, diabetes and cancer.  Excercise has been shown to counter inflammation. At the intersection of these processes, many of the methylation changes related to exercise and obesity are happening on genes that govern immune responses and inflammation.

Monday, February 4, 2013

Epigenetics, aging and cancer

We used to talk about how "the blueprint" for the human body was encoded in genes. These long chains of DNA held the instructions for the building of proteins, which made up the body's structures and carried its messages. End of story, right?  Actually, it's just the beginning.

Recent research has shown that genes, while crucially important, represent just one aspect of the human genetic system. The human body achieves its unique level of complexity by putting the same genes to many uses. In this light, mechanisms that "decide" when and where genes are turned on and off become central to human health and disease.

Interestingly, one set of these regulatory mechanisms, epigenetic changes, contribute to our genetic regulatory finesse without changing the instructions encoded in the DNA we inherit from our parents. Epigenetic mechanisms are chemical reactions that turn genes on and off during our lifespan, and largely thanks to our interactions with the world around us. Evidence is mounting that environmental factors like the foods we choose to eat constantly change the performance of our genetic material, and in ways that drive the aging process and cancer risk.

Such changes were the focus of a recent UAB Epigenetics Symposium, and The Mix – the UAB research blog – sat down with some of the presenters. Today's guest is Trygve Tollefsbol, Ph.D., professor of in the UAB Department of Biology, and an expert on the relationships between epigenetics, cancer and aging.


Show notes for the podcast: 

:53 Epigenetics is defined as changes in human gene expression caused not by changes in the order of base pairs, the DNA "letters" making up our genes. Epigenetic changes are instead the result of chemical reactions that determine whether or not the instructions encoded in a given stretch of DNA are read and followed..

2:20 If a person is born with a cancer-causing mutation, a permanent change in the order their DNA code within a gene, current medicine cannot often or easily reverse it. Physicians try to treat the cancer, but cannot easily address the underlying genetic problem.

2:39 One of the most exciting things about epigenetic changes, Tollefsbol said, is that they are easily reversible. Researchers hope they will soon be able to manipulate epigenetic mechanisms to reverse disease processes. This becomes especially relevant when you consider that perhaps "half of cancer cases" are caused by epigenetic changes instead of mutations in the DNA code, Tollefsbol said.

3:54 Two important epigenetic mechanisms that regulate when genes are turned on or off are DNA methylation and histone acetylation. Methylation is the chemical attachment at a certain point on the DNA chain of a methyl group (one carbon atom bonded to three hydrogen atoms). This attachment can make it possible for other proteins to bind to the DNA chain such that the surrounding gene is silenced.

5:40 In addition, DNA does not just float around lose in the nuclei of human cells. Long chains of DNA are wrapped around protein "spools" that help to organize, protect and regulate them. Part of DNA regulation is spatial, and works by controlling when certain parts of DNA chains are able to unravel from their spools. The unraveling makes a stretch of code accessible to the protein-making machinery. The spools are proteins called histones, and the attachment of an acetyl group (a methyl group plus an oxygen) to a histone tends to make genes on that spool more accessible.

6:50  Enzymes, protein catalysts in the body, which encourage epigenetic changes include DNA methylase and histone acetyltransferase. They serve as editors of the proteins that are controlling gene expression. Researchers in the future may be able to manipulate such enzymes with drugs that reverse epigenetic processes contributing to many diseases.

8:26 Epigenetics is a central interest in Tollefbol's lab, especially with respect to cancer and aging.  His team is interested in countering the epigenetic changes that contribute to the aging process, many of which appear to be influenced by diet. Both the quality and the quantity of the food we eat affects our gene expression. Evidence is mounting that caloric restriction, the hard choice to consume fewer calories, contributes to longer life and protects against cancer through epigenetic processes.

10:47  Whether or not a person gets cancer as they age in part comes down to a battle between genetic mechanisms that encourage cell growth (and that get broken to create abnormal growth) and others that suppress tumors by countering growth. It's a gas pedal versus the brakes. Evidence is emerging that epigenetic changes brought about by environmental factors (diet, sunlight exposure, air quality) can shift the balance from health toward disease as we age.

12:10  In the car analogy, oncogenes are the gas pedal for abnormal growth, while tumor suppressor genes are the brakes. Oncogenes encourage cell division. Each cell divides to become two, the number of cells goes up and growth occurs. Tumor suppressors block cell division. Taking the car analogy further, one then has to consider how much gas is in the tank. DNA within a human cell, packaged in chromosomes, can be copied into a new generation of cells only so many times. Each time a cell divides, the tail end of the chromosome called the telomere gets a little shorter until it is gone. Like the amount of gas in a tank, this serves as a physical limit on cell division, limiting the lifespan of a line of cells and its ability to drive tissue growth. Limited telomere length also serves as another protection against tumors as cancer cells seek to become immortal.

12:27 The older we get, the more likely we are to acquire problems with telomerase, the enzyme that sets telomere length in the womb, and then shuts down in most normal adult cells. Cancer cells are "addicted" to telomerase, which extends the length of their telomeres indefinitely. This fills the gas tank and makes the cells "immortal" as they divide and multiply indefinitely. Evidence suggest that many of the mechanisms that contribute to abnormal telomerase activity are epigenetic chemical modifications, said Tollefsbol.

14:02 While telomeres get shorter and shorter as a measure of aging, you can't just give telomerase to a person and think they will live for seven hundred years.The same process that causes aging via the suppression of telomerase after we leave the womb protects us from cancer.

15:29 Drug designers have seized on the realization that cancer cells depend on telomerase to become immortal and that normal cells don't use it. Selective telomerase inhibitors have been developed and some are in clinical trails. While the arrival of effective drugs in this class would be a boon, Tollefsbol's lab has determined that many compounds in common foods epigenetically prevent the activation of telomerase.  Broccoli, Brussels sprouts, cabbage, green tea and avocados are examples of foods containing compound that epigenetically turn of the gene that encodes telomerase.

17:37  The main thrust of Tollefsbol's presentation at the recent UAB Epigenetics Symposium was the concept of the "Epigenetics Diet," a term coined by his team. Specifically, Tollefsbol and colleagues are looking closely at the action of the chemical called solforaphane found in broccoli, cabbage and Kale that has beneficial epigenetic effects, including the turning down of the gene that expresses telomerase. While long-term studies need to be done, it may that eating more of these foods from childhood on protects a person against cancer later in life.

19:17 Tollefsbol also presented the results of a study that showed feeding isolated human cells less sugar (caloric restriction) not only enabled the cells to live longer but also to killed precancerous cells in their midst via epigenetic mechanisms. The finding may have implications for ongoing public health and policy debates surrounding the proposed causes of the U.S. obesity epidemic and potential remedies.