Epigenetics: Half of the picture (PART 1)

Science plugs stem cells into epigenetic opportunities that control various disease states

Kimberely Sirk
There are a couple schools of thought on how diseases begin.In modern genetics,  science says thatissues 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 betested for now. You may soon be able to evaluate your own genome through anat-home test.
 
The field of epigenetics, on the other hand, involves changesthat impact our DNA, but are not guided by inheritance. These are guided byother factors, such as environment.
 
In every article describing the leaders in the field,perhaps no institution is more prolific than Johns Hopkins University. One ofthis 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 andhas published widely on the subject.
Google the topic "epigenetics," and itwon't be long before you encounter his name.
 
Cancer is still one of the most intractable diseases knownto man—yet Baylin is hopeful that the emerging field of epigenetics is spawningfresh hope for a cure, and not just "someday."
Baylin also provides the neatest and most conciseexplanation of epigenetics: "Think of DNA as the hard drive of the cell," hesays. "Epigenetics is the software package."
 
When it comes to the ever-evolving world of stem cellresearch, stem cells are important to epigenetics because they have uniqueepigenetic characteristics that make them different from other cells. If stemcells lose their own epigenetic programming, they are no longer stem cells.They might become a differentiated cell or even a cancer cell. Many drugs areknown to target the so-called "epigenome" of cells, and science is pursuing howto use these drugs to control cell behavior. That includes stem cells.
 
In this, the first part of a two-part series on trends instem cell research, we will examine the intersection where stem cells andepigenetics meet, and how scientific progress in this field will yield thedevelopment of therapies.
 
How do epigeneticchanges happen?
 
Epigenetics controls nearly every aspect of the biology ofevery type of stem cell.
Epigenetics regulates if the information in DNA can beturned into some sort of action. Cells have machinery that turns theinformation stored in DNA into functional RNAs and proteins, but it isepigenetics that determines whether that machinery is allowed to do its job.
 
Epigenetics has two main elements: DNA methylation andhistone modifications. These elements control how the DNA is structured, andthe structure of DNA determines its function.
DNA methylation is a modified form of DNA typicallyassociated with a resting state. Thus, DNA methylation is a type of epigeneticfunction that turns down the "thermostat" of DNA activity.
Histone modifications manifest themselves in a wide varietyof ways. They either ramp up DNA or tone it down. What the histones do to theDNA structure depends on how they are modified.
 
All of these changes directly determine how active the DNAis in specific regions, such as in the genes. But science is years away fromthese therapies making the jump to clinical use—in most cases.
 
At the recently concluded American Society of ClinicalOncology (ASCO) conference, a small but growing number of presentations weremade about epigenetic research. In the daily conference briefings, severalcommentators took note of posters and presentations on some issues inepigenetics, including applications in pediatrics. Most of these presentationswere at the very beginnings of clinical investigation, but they addressed bothliquid and solid-tumor cancers, including breast, prostate and colorectalcancers, as well as T-cell lymphoma.
 
Types of stem cells
 
There are several key types of stem cells. These types havedifferent benefits and challenges—some political and some chemical. Science isracing to plug these stem cells into epigenetic opportunities that controlvarious disease states.
 
Stem cells fall into four basic types, with two differentmechanisms of action. Stem cells can be either pluripotent or multipotent. Thetwo key types being pursued now are mesenchymal stem cells (MSCs) or inducedpluripotent stem cells (iPSCs). MSCs are found in bone marrow, adipose tissue(or fat), umbilical cord blood or peripheral blood. These cells can become newbone or cartilage, fat, muscle or pancreatic beta cells. These cells, likeiPSCs, have differentiation potential, meaning that they can turn into any typeof cell. IPSCs, though, have various sources and can become any adult celltype.
Epigenetics is important for stem cells because of cellularreprogramming. When scientists make iPSCs, they are reprogramming the epigenomeof a non-stem cell into that of a stem cell. Remarkably, the entire cell nowtakes on the identity of a stem cell.
 
The epigenome guidescell behavior
 
The cell, in turn, has no choice but to accept these changesand either alter its behavior or die. Of course, the process does not always goas one might hope, and sometimes, since epigenetic changes are not complete,cellular reprogramming is not complete. Instead of iPSCs, you get pre-iPSCs, orany of many other cell types.
 
To learn more about the basics of epigenetics, we spoke withDr. Michael Skinner, a basic science researcher at Washington State University.Skinner's research in the field of epigenetics has been widely published formore than 20 years, but just recently, is he finding his phone ringing moreoften due to a building interest in epigenetics.
He's a systems biologist—he studies environmentalepigenetics and reproductive effects of substances on development and functionon molecular, cellular and physiological levels. Skinner is also basic scienceresearcher. His research projects investigate how different cell types inanimal tissue interact and communicate to regulate cellular growth anddifferentiation. His area of emphasis is reproductive biology, so he's huntingfor 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 areason to look further to prove or disprove a hypothesis in humans.
 
More recently, Skinner and colleagues have turned theirattention to the ability of environmental factors to act on gonadal developmentto cause epigenetic transgenerational, adult-onset disease and influence areasof biology such as evolution. This has now become a predominant research thrustin his lab. His basic research projects involve the investigation of howdifferent cell types in a tissue interact and communicate to regulate cellulargrowth and differentiation, with emphasis in the area of reproductive biology.
After a finding in Skinner's lab, the investigation picks upwith an environmental toxicologist.
 
In genetics, changes passed down through generations comefrom DNA. In epigenetics—back to Baylin's software reference—changes can switchdepending on some other factor. Software packages can be updated, upgraded andloaded to replace what was there before or add something new. What Skinner'swork is telling us is that environmental exposure that suggests epigeneticexposure can ripple through generations. In scientific parlayance, this isknown as epigenetic transgenerational inheritance.
Many of the chemicals widely in use today span threegenerations of use in our environment.
 
For example, Skinner has researched vinclozolin, a popularfruit and vegetable fungicide known to disrupt hormones and have effects acrossgenerations of animals. This is the research he did with the rats and their third-generationdescendants, and his findings suggest that stress and anxiety effects seen inthe newest generation resulted from changes in the grandparents.
 
"The ancestral exposure of your great-grandmother altersyour brain development to then respond to stress differently," Skinner recentlytold ScienceDaily. "We did not know astress response could be programmed by your ancestors' environmentalexposures."
 
Skinner has published widely on this topic. He's publishedon transgenerational effects of environmental factors, such as pesticides,plastics and environmental compounds, showing significant amplification of theimpact and health hazards of these chemicals over time. The transgenerationalnature suggests that a permanent epigenetic alteration of the germ-line in thesubjects studied has taken place.
 
Skinner says he has studied a half-dozen compounds that arefound in the environment and considered common due to human activity. Some ofhis most remarkable work includes studying the compound Bisphenol A (BPA), acomponent of plastic. At the request of the military, he studied jet fuel—ahydrocarbon and another widespread chemical.
 
The jet fuel Skinner studies is an aviation fuel known asJP8. What that study was looking for was a suggestion of a negative biologicalresult from the practice of spraying JP8 onto dusty roads around military basesto compact the dust.
 
JP8, just to be clear, is very different that the stuff youpump into your gas tank. The study of JP8 in animals found the sametransgenerational link to basic biological changes that the pesticide studydid.
 
In addition to effects on reproduction, numerous otheradult-onset diseases are observed, including cancer, prostate disease, kidneydisease, immune abnormalities and behavior effects. Further characterization ofthis phenomena and its impact on disease etiology and evolutionary biology isin progress, by Skinner and others.
 
Basically, Skinner says, epigenetic changes happen at thevery basic levels of life. When a zygote is formed biologically, the cellsdemethylate for a time, where changes that are not dictated by DNA can occur.
 
Demethylation is one of the critical concepts. In thatprocess, the cell stands waiting. Aside from Skinner's pointing out that thishappens right after conception, demethylation is being studied for otheropportunities.
 
For example, at ASCO, a paper was presented about testingtargeted demethylation to overcome resistance to epidermal growth factorblocking agents in colorectal cancer. Again, this peels back a layer of commonunderstanding of taking a medicine with a known behavior to curedisease—science is boring down into how diseases alter or take hold of ourcells.
 

Kimberely Sirk

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