By Sarah (Steve) Mosko
Special to the Surf City Voice
What if chemicals your great-great grandmother was exposed to, or even her diet, could affect your risk of falling victim to cancers, mental illness or Alzheimer’s disease? Sounds far-fetched perhaps, but what we are learning about the new science of epigenetics says it’s very possible and happens without a change to the DNA you inherited from her.
Epigenetics also explains how it is that your brain and toe are made of cells with identical DNA, but look and function so differently, and why identical twins are never exact replicas, though their DNA is.
The basis for all these phenomena lies not in the genome – the DNA sequences which make up our genes – but rather in intricate cell machinery sitting atop the DNA that dictates which genes are turned on or off at any point in the life of both a single cell or an entire organism, like a human being. A good analogy would be the orchestra conductor signaling when each instrument should play and how loudly. The Greek prefix “epi” means “on top of” or “in addition to,” hence the epigenome denotes the apparatus attached to the genome within a cell’s nucleus which enables tissues and even whole organisms with identical DNA to look and function very differently.
It’s long been appreciated that the epigenome is what coordinates the development of a fetus, telling an undifferentiated stem cell, for example, to morph into a heart cell at the right time. Because the epigenome is replicated along with the DNA during cell division, it also provides the “cell memory” needed so the heart cell knows to keep making more heart cells.
However, what’s new and creating shockwaves in our understanding of human illnesses is that the epigenome is influenced throughout our lifetime by not only normal internal factors, such as hormones, but by external ones too, like diet, drugs, stress and environmental pollutants. An epigenome that can adjust to changes in environmental conditions, like a scarcity of food, is advantageous if the adjustments enable better adaptation to the environment. However, a non-fixed epigenome also means that conditions you were exposed to early in development which modified the epigenome in unfortunate ways might trigger diseases cropping up even decades later in adulthood.
Moreover, where we used to assume that any acquired epigenetic changes were erased during the type of cell division that produces eggs and sperm, we know now that eggs and sperm can also retain acquired epigenetic markings which, good or bad, can be passed on to your children and your children’s children.
The Epigenetic Machinery
The human genome is comprised of 20-25,000 genes, but by far the majority are turned off in differentiated cells through various epigenetic means. Significant progress has been made in recent years in understanding two particular epigenetic mechanisms and how they relate to human diseases.
The most studied is called DNA methylation where methyl groups (CH3) – a common chemical structure in foods and vitamins – attach directly onto the strands of DNA, like charms on a chain-link bracelet, and have the effect of silencing genes. The importance of DNA methylation is illustrated by the fact that, during the normal development of an embryo, DNA undergoes critical waves of both methylation and de-methylation which orchestrate healthy cell growth and differentiation.
The other epigenetic mechanism, so-called histone modification, is a bit more convoluted. DNA strands are very long – a single strand is made of tens of millions of the building block base nucleotides. Consequently, nature has developed a system of packaging the DNA that both keeps it compact and regulates which parts are available, or not, for transcription.
Proteins called histones group together to form spool-like structures around which the DNA is wrapped, much like threads on a spool. DNA that is tightly wrapped is generally inaccessible for read-out and so is repressed. In the parlance of geneticists, such DNA sections are “closed.” In contrast, loosely wrapped DNA is “open” and the genes in those areas are generally active.
The histones determine how the DNA wraps around them by way of “histone tails” that stick out and are available to be tagged by chemical factors floating by. Depending on what factors latch on and where, the histone shape is modified which, in turn, affects whether the DNA is open or closed.
For instance, an “acetyl” tag (COCH3) on a histone tail generally opens up the adjacent DNA for read-out, whereas removing or replacing an acetyl tag with a different factor can have the opposite effect. Acetyl is another very common chemical structure found, for example, in acetaminophen, aspirin (acetylsalicylic acid) and heroin (diacetylmorphine).
Unless a mutation occurs, the DNA sequence remains fixed for the life of a cell. However, both DNA methylation and histone tail modifications are, by design, changeable and consequently sensitive to the cell’s environment. So for a whole organism like a human being, anything which affects the chemical soup inside its cells can potentially alter which genes are expressed and, thus, the health of the whole organism. Scientists are just now getting an idea of the wide spectrum of environmental factors which could be shaping the human epigenome.
It goes without saying that a person’s DNA determines vulnerability to many ailments through either inherited genes or, occasionally, new DNA mutations. A clear-cut example would be Huntington’s disease, a neurodegenerative condition where a child inheriting a single defective gene from either parent with the disease will also be afflicted 100 percent of the time.
The realization that the epigenome also plays a role in many illnesses grew, in part, out of the observation that some ailments appear at certain ages, suggesting a switch of some sort had been flipped. For example, symptoms of schizophrenia rarely appear before adolescence, and the onset of Huntington’s disease is usually delayed until after the age of 35. Scientists suspect that the epigenome keeps the defective gene(s) in check early on, but that epigenetic changes accumulate gradually over time so the defect is eventually unmasked and the person falls ill.
Experts think that a build up of epigenetic changes also explains why one identical twin develops a disease and the other does not. When the epigenomes of twins are compared, the epigenetic markings are essentially identical as toddlers, but become much less similar as time goes on and their vulnerabilities to illnesses also diverge. Schizophrenia is one disorder known to run in families and has a strong genetic basis, so researchers are actively looking into and finding patterns of DNA methylation and histone modifications of the suspect genes that could explain why nearly half the time when one twin is afflicted the other is spared.
In autoimmune diseases like multiple sclerosis, rheumatoid arthritis and lupus, the frequency of the second twin falling victim too when one has the condition is much lower, between one in four and one in eight. This suggests that a genetically inherited susceptibility is only part of the story, and researchers have found the epigenome fertile ground for hints to the rest. Take lupus, for instance, a condition where the body’s immune system goes haywire and attacks the skin, joints and/or internal organs. No one gene causes the disease, but more than 20 which participate have already been identified. The known environmental triggers are ones that damage cells (like ultraviolet light, viruses and certain drugs), thus exposing the immune system to novel cell components normally locked away within the nucleus. There is compelling evidence that environmental triggers act through DNA de-methylation of so-called T-cells, the foot soldiers of the immune system that consequently go renegade and mistake normal cell components for foreign invaders. The T-cells of people with lupus have the same pattern of de-methylation as do T-cells exposed to drugs known to both inhibit DNA methylation and set off lupus symptoms.
Alzheimer’s disease is the most common form of dementia, affecting one in 16 people after the age of 65. Post-mortem brain analyses reveal extensive atrophy with a signature buildup of abnormal deposits called plaques and tangles. The vast majority of cases are sporadic, meaning the disease does not run in families and can’t be tied to particular genes, which has led geneticists to turn to the epigenome for answers. What they are finding is described as “epigenetic drift,” a gradual accumulation of many epigenetic changes spread throughout the genome, affecting both genes that protect against Alzheimer’s and others that add risk. Because the brains available for study are generally from persons with very advanced stages of the disease, it’s not yet certain whether epigenetic drift is the cause or the consequence of the disease.
Nevertheless, the current thinking is that as yet unidentified environmental factors spur epigenetic changes pivotal to the onset of the disease, and this notion has traction from studies showing that a healthy diet (like the Mediterranean diet which is rich in fruits, vegetables and omega-3 fatty acids), physical exercise and married lifestyle (i.e. co-habitation) are the best known defenses. Among the specific nutritional components that could be involved are vitamins B12, B6 and folate because they are good methyl group sources, and diets deficient in these substances increase risk for Alzheimer’s. Coffee drinking and long-term use of nonsteroidal anti-inflammatory drugs, like aspirin and ibuprofen, also seem to be protective, whereas cigarette smoking increases risk.
Epigenetic drift is also characteristic of normal aging, which probably explains why aging is, by itself, the greatest risk factor for Alzheimer’s. A global loss in DNA methylation occurs during aging, and animal studies suggest that longer lifespan is correlated with slowed DNA de-methylation. Scientists suspect that dietary calorie restriction, the only intervention in mammals shown to increase lifespan, likely acts through epigenetic modifications that slow a normal age-related loss of a family of proteins that seem to keep cells younger.
Cancer begins with a DNA mutation, but a wealth of recent research is pointing to a major role of epigenetics in cancers too. For example, many types of cancer cells have been found to have an abnormal pattern of methylation where the DNA is globally under-methylated but certain genes – like ones that repair DNA or normally prevent cell growth from getting out of hand – are blocked by local excess methylation. The list of cancers already linked to abnormal DNA methylation of specific genes is expanding rapidly and includes lung, ovarian, breast, endometrial, bladder, esophagus, stomach, intestinal, colon and melanoma as well as blood cancers like lymphoma, leukemia and myelodysplastic syndrome. The number of cancers associated with specific histone modifications is nearly as large.
Epigenetic Inheritance & Environmental Influences
The idea that physical or behavioral traits acquired during one’s lifetime could be handed down to the next generation was, until very recently, relegated by modern geneticists to the trash heap. As example of the kind of experiment that discredited this notion, the offspring of mice whose tails have been chopped short are always born with normal length tails.
However, recent experiments have demonstrated that traits acquired through alterations in the epigenome are sometimes passed on in eggs or sperm via epigenetic inheritance. One striking example revolves around a mouse gene variant dubbed the agouti where the gene’s pattern of methylation determines both coat color and health. In the hypo-methylated state, agouti mice are born yellow and become obese and prone to tumors and diabetes. Methylation silences the agouti gene, producing thin brown rats with few tumors.
One astounding aspect of the agouti story is that just manipulating how rich a pregnant mouse’s diet is in sources of methyl groups influences whether the offspring are born of the brown or yellow type. That diet alone could induce epigenetic changes which affect susceptibility to illness is very intriguing given that the incidence of several cancers, heart disease, diabetes and many other human conditions are already known to be influenced by diet. The other astonishing finding is that the mother’s (and even grandmother’s) coat color determined the likelihood pups were born brown or yellow, showing that the methylation pattern in eggs cells was not reset but rather retained through another generation.
In humans, evidence is accruing that diet – in this case the availability of food – early in development influences whether a person develops schizophrenia. Parts of China experienced a severe famine affecting tens of millions of people from 1959 to 1961. An epidemiological study has shown that babies born during this period were at more than double the risk for eventually developing schizophrenia. Although how an early famine diet would foster schizophrenia is not yet known, a twin study reported in 2011, which links both schizophrenia and bipolar disorder to altered methylation at some key genes in the affected twin, has scientists thinking that famine might act through the epigenome.
Synthetic chemicals in the environment are an obvious place to look for environmental influences on the epigenome. In 2005, the first study was published demonstrating that fetal exposure to an environmental toxin could trigger illness in adulthood through an epigenetic mechanism and that subsequent, unexposed generations are also affected. Researchers at Washington State University found that pregnant rats exposed to a common fungicide or pesticide known to mimic or block sex hormones produced, through altered DNA methylation, sons, grandsons, great-grandsons and even great-great-grandsons with low sperm counts and reduced fertility.
Follow-up studies revealed that, by a similar epigenetic mechanism, brief fungicide exposure during fetal life also conferred increased risk for several diseases of aging in both male and female rats across multiple succeeding generations. The afflictions most often passed on included kidney and prostate diseases, testis abnormalities, and tumors of the breast, lung and skin.
The applicability of such findings to humans is unclear, especially given that the chemical doses used were rather high, but subsequent research on other environmental contaminants has only intensified concern that prenatal exposure can instigate epigenetic changes with harmful effects appearing later in life.
In a University of Illinois study for example, fetal male rats exposed to the estrogen-mimicking chemical bisphenol A (found in plastics and the lining of canned foods) subsequently developed early signs of prostrate cancer, with evidence pointing to altered DNA methylation of a gene linked to prostate cancer as the likely mechanism. Importantly, the dose of bisphenol A used was low and produced tissue levels comparable to those commonly seen in people.
Recent investigations have made clear that remodeling of the epigenome can occur in response to environmental factors far more subtle than toxic chemicals and should be considered as a candidate means through which most any environmental factor influences the physical characteristics or behaviors of animals and humans. For instance, studies in rats have shown that the quality of maternal care – defined as the amount of licking and grooming a pup receives from its mother in the first week after birth – permanently imprints the epigenome (through processes including DNA de-methylation and histone acetylation) and determines how the animals react to stress as adults. Researchers are positing that analogous early epigenomic imprinting might explain how children deprived of adequate parental care can exhibit severe cognitive and behavioral problems persisting into adulthood.
The Future of Epigenetics
A bedrock tenet of evolutionary biology has been that evolution occurs very slowly as a consequence of rare and random changes to the genetic code and that those changes which foster better adaptation to the environment get passed on the most. Epigenetics is turning this notion on its head because epigenetic changes are neither random nor do they involve the genetic code, and the interplay with the environment is different because the environment instigates rapid changes to the epigenome throughout one’s lifetime that can be inherited by future generations.
Even though our understanding of epigenetics is in its infancy, how we conceptualize the evolution of all life forms, including our own, is already transformed. We should also expect that epigenetics will revolutionize the entire field of medicine. Scientists have begun looking into how epigenetic markers might be used to catch diseases earlier on and to predict how well a given treatment, like chemotherapy, will work. A new generation of pharmaceuticals which manipulate the epigenome to switch targeted genes on or off is under investigation too, and the new field of “nutragenomics” is gaining credibility as a means to repair or optimize the epigenome through diet alone.
The most important shift in our thinking, however, will hopefully come from a much deeper and sorely needed respect for how tied our own future as a species is to the state of the environment. Western society tends to see humans as somehow outside of or even in conflict with nature, hence the ease with which we find convenient excuses for polluting the air, soil and water. Perhaps the core lesson to be learned from epigenetics is that there is no real boundary between us and the rest of nature. We are, literally, everything we eat, drink, breathe in and absorb through our skins. We are inseparable from the environment and should tend to it with the same care we give to raising children.