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Epigenetics: Half of the picture (PART 1)
July 2012
by Kimberley Sirk  |  Email the author
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There are a couple schools of thought on how diseases begin. In modern genetics,  science says that issues with our genes will govern whether or not we get sick in the future. Remember hearing a few years back about how the entire human genome is now "mapped?" This map can tell us a lot about disease.
 
For example, there are two breast cancer genes that can be tested for now. You may soon be able to evaluate your own genome through an at-home test.
 
The field of epigenetics, on the other hand, involves changes that impact our DNA, but are not guided by inheritance. These are guided by other factors, such as environment.
 
In every article describing the leaders in the field, perhaps no institution is more prolific than Johns Hopkins University. One of this academic institution's "rock-star docs" is Dr. Stephen Baylin, a physician, who tops most lists of the giants in the field. Baylin, a physician, is a prolific researcher and has published widely on the subject.
Google the topic "epigenetics," and it won't be long before you encounter his name.
 
Cancer is still one of the most intractable diseases known to man—yet Baylin is hopeful that the emerging field of epigenetics is spawning fresh hope for a cure, and not just "someday." Baylin also provides the neatest and most concise explanation of epigenetics: "Think of DNA as the hard drive of the cell," he says. "Epigenetics is the software package."
 
When it comes to the ever-evolving world of stem cell research, stem cells are important to epigenetics because they have unique epigenetic characteristics that make them different from other cells. If stem cells lose their own epigenetic programming, they are no longer stem cells. They might become a differentiated cell or even a cancer cell. Many drugs are known to target the so-called "epigenome" of cells, and science is pursuing how to use these drugs to control cell behavior. That includes stem cells.
 
In this, the first part of a two-part series on trends in stem cell research, we will examine the intersection where stem cells and epigenetics meet, and how scientific progress in this field will yield the development of therapies.
 
How do epigenetic changes happen?
 
Epigenetics controls nearly every aspect of the biology of every type of stem cell. Epigenetics regulates if the information in DNA can be turned into some sort of action. Cells have machinery that turns the information stored in DNA into functional RNAs and proteins, but it is epigenetics that determines whether that machinery is allowed to do its job.
 
Epigenetics has two main elements: DNA methylation and histone modifications. These elements control how the DNA is structured, and the structure of DNA determines its function. DNA methylation is a modified form of DNA typically associated with a resting state. Thus, DNA methylation is a type of epigenetic function that turns down the "thermostat" of DNA activity. Histone modifications manifest themselves in a wide variety of ways. They either ramp up DNA or tone it down. What the histones do to the DNA structure depends on how they are modified.
 
All of these changes directly determine how active the DNA is in specific regions, such as in the genes. But science is years away from these therapies making the jump to clinical use—in most cases.
 
At the recently concluded American Society of Clinical Oncology (ASCO) conference, a small but growing number of presentations were made about epigenetic research. In the daily conference briefings, several commentators took note of posters and presentations on some issues in epigenetics, including applications in pediatrics. Most of these presentations were at the very beginnings of clinical investigation, but they addressed both liquid and solid-tumor cancers, including breast, prostate and colorectal cancers, as well as T-cell lymphoma.
 
Types of stem cells
 
There are several key types of stem cells. These types have different benefits and challenges—some political and some chemical. Science is racing to plug these stem cells into epigenetic opportunities that control various disease states.
 
Stem cells fall into four basic types, with two different mechanisms of action. Stem cells can be either pluripotent or multipotent. The two key types being pursued now are mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs). MSCs are found in bone marrow, adipose tissue (or fat), umbilical cord blood or peripheral blood. These cells can become new bone or cartilage, fat, muscle or pancreatic beta cells. These cells, like iPSCs, have differentiation potential, meaning that they can turn into any type of cell. IPSCs, though, have various sources and can become any adult cell type. Epigenetics is important for stem cells because of cellular reprogramming. When scientists make iPSCs, they are reprogramming the epigenome of a non-stem cell into that of a stem cell. Remarkably, the entire cell now takes on the identity of a stem cell.
 
The epigenome guides cell behavior
 
The cell, in turn, has no choice but to accept these changes and either alter its behavior or die. Of course, the process does not always go as one might hope, and sometimes, since epigenetic changes are not complete, cellular reprogramming is not complete. Instead of iPSCs, you get pre- iPSCs, or any of many other cell types.
 
To learn more about the basics of epigenetics, we spoke with Dr. Michael Skinner, a basic science researcher at Washington State University. Skinner's research in the field of epigenetics has been widely published for more than 20 years, but just recently, is he finding his phone ringing more often due to a building interest in epigenetics. He's a systems biologist—he studies environmental epigenetics and reproductive effects of substances on development and function on molecular, cellular and physiological levels. Skinner is also basic science researcher. His research projects investigate how different cell types in animal tissue interact and communicate to regulate cellular growth and differentiation. His area of emphasis is reproductive biology, so he's hunting for the very basic epigenetic changes that occur right after sperm meets egg. He conducts tests in animal models that can demonstrate that there may be a reason to look further to prove or disprove a hypothesis in humans.
 
More recently, Skinner and colleagues have turned their attention to the ability of environmental factors to act on gonadal development to cause epigenetic transgenerational, adult-onset disease and influence areas of biology such as evolution. This has now become a predominant research thrust in his lab. His basic research projects involve the investigation of how different cell types in a tissue interact and communicate to regulate cellular growth and differentiation, with emphasis in the area of reproductive biology. After a finding in Skinner's lab, the investigation picks up with an environmental toxicologist.
 
In genetics, changes passed down through generations come from DNA. In epigenetics—back to Baylin's software reference—changes can switch depending on some other factor. Software packages can be updated, upgraded and loaded to replace what was there before or add something new. What Skinner's work is telling us is that environmental exposure that suggests epigenetic exposure can ripple through generations. In scientific parlayance, this is known as epigenetic transgenerational inheritance. Many of the chemicals widely in use today span three generations of use in our environment.
 
For example, Skinner has researched vinclozolin, a popular fruit and vegetable fungicide known to disrupt hormones and have effects across generations of animals. This is the research he did with the rats and their third-generation descendants, and his findings suggest that stress and anxiety effects seen in the newest generation resulted from changes in the grandparents.
 
"The ancestral exposure of your great-grandmother alters your brain development to then respond to stress differently," Skinner recently told ScienceDaily. "We did not know a stress response could be programmed by your ancestors' environmental exposures."
 
Skinner has published widely on this topic. He's published on transgenerational effects of environmental factors, such as pesticides, plastics and environmental compounds, showing significant amplification of the impact and health hazards of these chemicals over time. The transgenerational nature suggests that a permanent epigenetic alteration of the germ-line in the subjects studied has taken place.
 
Skinner says he has studied a half-dozen compounds that are found in the environment and considered common due to human activity. Some of his most remarkable work includes studying the compound Bisphenol A (BPA), a component of plastic. At the request of the military, he studied jet fuel—a hydrocarbon and another widespread chemical.
 
The jet fuel Skinner studies is an aviation fuel known as JP8. What that study was looking for was a suggestion of a negative biological result from the practice of spraying JP8 onto dusty roads around military bases to compact the dust.
 
JP8, just to be clear, is very different that the stuff you pump into your gas tank. The study of JP8 in animals found the same transgenerational link to basic biological changes that the pesticide study did.
 
In addition to effects on reproduction, numerous other adult-onset diseases are observed, including cancer, prostate disease, kidney disease, immune abnormalities and behavior effects. Further characterization of this phenomena and its impact on disease etiology and evolutionary biology is in progress, by Skinner and others.
 
Basically, Skinner says, epigenetic changes happen at the very basic levels of life. When a zygote is formed biologically, the cells demethylate for a time, where changes that are not dictated by DNA can occur.
 
Demethylation is one of the critical concepts. In that process, the cell stands waiting. Aside from Skinner's pointing out that this happens right after conception, demethylation is being studied for other opportunities.
 
For example, at ASCO, a paper was presented about testing targeted demethylation to overcome resistance to epidermal growth factor blocking agents in colorectal cancer. Again, this peels back a layer of common understanding of taking a medicine with a known behavior to cure disease—science is boring down into how diseases alter or take hold of our cells.
 
 
Code: E071229

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