Environmental Epigenetics Has Potential For Preventing And Treating Disease

Daily Science Journal (Feb. 6, 2008) — New research on environmental influences on health and disease has begun to shed light on why genetically identical individuals demonstrate different characteristics, such as susceptibility to disease. Scientists have found that environmental exposure to nutritional, chemical and physical factors can alter the epigenome. Literally meaning “above the genome,” the epigenome refers to differences in gene expression that are inherited without changing the sequence of DNA.

New research* examines some of the epigenetic mechanisms linked to disease, and explores how they occur and their significance in understanding, treating and preventing disease.

Authors Randy L. Jirtle and Dana C. Dolinoy of Duke University Medical Center in Durham, North Carolina, discuss genomic imprinting, a form of gene regulation in which epigenetic modifications in chromosomes result in differences in gene expression. First identified in 1991, there are approximately 80 imprinted genes that have been identified in mice and humans. Because imprinted genes behave as if they have a single set of chromosomes rather than the usual two, the health consequences of mutations in these genes are potentially disastrous, resulting in diseases such as cancer and several severe pediatric developmental disorders.

In addition, mutations that occur in non-imprinted regions can influence the regulation of imprinted genes. The authors previously demonstrated that imprinting evolved anywhere from 230 to 150 million years ago, arising in mammals with the evolution of the placenta. They note that the expression of imprinted genes is species, tissue and developmental stage dependent and may play an important role in the speciation of mammals.

The article cites several studies involving metastable epialleles, which are alternate forms of a gene that are expressed due to epigenetic modifications linked to maternal nutrition and environmental exposure during very early development. The authors note that simple dietary changes were found to protect against the negative effects of environmental toxins on the fetal epigenome. They also cite evidence that embryos are vulnerable to environmentally-induced epigenetic alterations early in their development, highlighting the need to analyze the timing of exposure in order to fully understand environmental epigenomics.

The advent of bioinformatics has allowed researchers to more readily search the entire mouse genome for imprinted genes, but the real power of this approach has been recently demonstrated in its application to the human genome. While 2.5 percent of the mouse genome contains potentially imprinted genes, only 0.75 percent of the human genome is predicted to be imprinted. This means that the mouse genome may not be a suitable model for assessing human disease risk due to epigenetic mutations in imprinted genes. The authors point out the necessity of developing bioinformatic models that can identify metastable epialleles in order to characterize all of the genes susceptible to environmental influences.

With the identification of epigenetically unstable locations in the human genome, it will be possible to screen individuals at an early age for epigenetically susceptible diseases, allowing for closer monitoring and more frequent follow-up. In addition, unlike genetic mutation, epigenetic profiles are potentially reversible. “Therefore, epigenetic approaches for prevention and treatment, such as nutritional supplementation and/or pharmaceutical therapies may be developed to counteract negative epigenomic profiles,” the authors conclude. “The future of epigenomics therapy holds tremendous potential for not only individualized health care but also for population-wide disease diagnostic, screening, and prevention strategies.”

*Article: “Environmental Epigenomics in Human Health and Disease,” Dana C. Dolinoy and Randy L. Jirtle, Environmental and Molecular Mutagenesis, January 2008, 49:1.

Adapted from materials provided by Blackwell Publishing Ltd.

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Medicine From Milk: Gene Therapy Transforms Goats Into Pharmaceutical Factories

Daily Science Journal (Feb. 1, 2008) — University of Pennsylvania researchers have used gene therapy to reduce the time it takes to breed large animals capable of producing therapeutic proteins in their milk, such as insulin or those that fight cancer. This represents a significant milestone in drug development, as current methods involve cloning, which takes more time and generally costs more.

Researchers have used gene therapy to reduce the time it takes to breed goats capable of producing therapeutic proteins in their milk, such as insulin or those that fight cancer. (Credit: iStockphoto)

"Having an easier way to harness nature's power to produce large quantities of specific proteins in milk could increase the availability of drugs for people who could otherwise not afford these treatments," said Ina Dobrinski, one of the researchers on the study.

The study also is significant because it may also be a new way to eliminate diseases in future generations of animals, such as those used for livestock. Here's why: To get the goats to produce specific proteins, the researchers used radiation to kill a portion of a male goat's germ cells (the cells that produce sperm). Then they used a modified adeno-associated virus (a well studied and tolerated gene therapy vector) to insert a gene in the remaining cells. Once the new gene took hold in the germ cells, a predictable number of female offspring produced the desired protein in their milk.

The advance is immediately valuable for pharmaceutical development and biology research, but a similar approach could be used to bolster the food supply by eliminating genetic disorders in animals over several generations. It is also possible that once perfected, this technique could eliminate disease genes in humans over several generations, assuming ethical concerns can be resolved adequately.

This study is published in the February 2008 print edition of The FASEB Journal.

"For thousands of years, people have domesticated cows and goats to make milk, butter and cheese. And for thousands of years dairy products have been used as folk remedies for practically every human illness. Most have been completely ineffective." said Gerald Weissmann, MD, editor-in-chief of The FASEB Journal. "So it is reassuring that modern science would find a way to use the milk we drink to yield of drugs that actually work."

Adapted from materials provided by Federation of American Societies for Experimental Biology, via EurekAlert!, a service of AAAS.

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New Gene Linked To Fragile X Syndrome -- Suggests Potential Targets For Autism And Other Neurological Disorders

Daily Science Journal (Feb. 1, 2008) — Scientists at The Scripps Research Institute have discovered a new gene involved in fragile X syndrome, a condition that often shares many symptoms of autism. The discovery may lead to new tests or treatments for several neurological disorders.

The new gene has been dubbed FMR4. "FMR4 is a novel gene that is located in the same chromosomal neighborhood as FMR1, a well established causative gene in fragile X syndrome," said Claes Wahlestedt, a professor at the Scripps Research campus in Jupiter, Florida. "Like FMR1, FMR4 is silenced in fragile X patients and up-regulated in FXTAS (fragile X-associated tremor/ataxia syndrome), a disease that resembles Parkinson's disease. Our discovery could lead to the development of new diagnostic tests or even to novel therapies for these defects."

Fragile X syndrome affects thousands of patients worldwide with severe learning disabilities, often accompanied by anxiety disorders, obsessive-compulsive behavior, and attention deficit hyperactivity disorder. There are currently no therapeutic treatments available for fragile X syndrome. Approximately one-third of all children diagnosed with fragile X syndrome also have some degree of autism, according to The National Fragile X Foundation, including such behaviors as social anxiety, poor eye contact, and hand biting.

More than 16 years ago, scientists linked fragile X syndrome to inactivation of FMR1 gene expression, leading to the lack of a protein known as the fragile X mental retardation protein, now considered to be critical for neuronal function. Until the current study, no other functional gene other than FMR1 had been shown to be inactivated in the disorder.

However, Wahlestedt knew the FMR1 gene locus-a specific point on a chromosome-was not well mapped. Wahlestedt and his colleagues hypothesized that unknown regulatory genes might be transcribed from the region.

The new study shows at least one other functional gene-FMR4-from this genetic region is linked to fragile X syndrome, although the gene's exact role in the intact brain remains uncharacterized..

"FMR4 is the new neighbor on the block and should not be ignored," Wahlestedt said. "While there is no direct relationship between these two genes [FMR1 and FMR4] that we know of, our study shows that FMR4 is not a conventional gene-it's a non-coding RNA transcript. It's not a dead piece of the genome, it has a pronounced functional effect in human cultured cells.."

The Role of Non-coding RNA

Non-coding RNA (ncRNA) transcripts or genes produce functional RNA molecules (ncRNAs) rather than encoding proteins. These ncRNAs are active in a number of different processes, including RNA modification, chromosome replication, and protein degradation.

A number of studies have suggested that at least 40 to 50 percent of the mammalian genome becomes transcribed, Wahlestedt pointed out, but only one to two percent of these transcripts are translated into proteins. "Several studies suggest that some ncRNA genes can be involved in various human diseases," he said. "FMR4 certainly falls into that category."

According to the study, FMR4 directly affects human cell proliferation in vitro-when the gene is silenced, changes in the cell cycle and a rise in apoptosis or programmed cell death occur. Overexpression, on the other hand, leads to increased cell proliferation.

The full meaning of this anti-apoptosis function is still unclear. "It could be critical for some cells to live or die at a certain stage in development, but we don't know what cells those might be," Wahlestedt added. "The fact that FMR4 is widely expressed in the human brain in both embryos and adults may possibly indicate a broad function."

The new study underscores the growing awareness among scientists of the complexity and unpredictability of the human genome.

"We know now that our genome is very busy and very complicated," Wahlestedt said "A great deal of this newly found complexity is about the regulation of other genes. As evolution has progressed, particularly in the higher organisms, there has been a corresponding increase in the need for regulatory mechanisms-to maintain more control over genome. Non-coding RNAs are at the center of these regulatory mechanisms."

The FMR4 discovery also highlights the mission of The Translational Research Institute at Scripps Florida, which is focused on translating basic research like the discovery of FMR4 into potential new therapeutics. The Translational Research Institute has a structure similar to a drug discovery company, and many of the researchers have pharmaceutical experience.

In addition to Wahlestedt, other authors of the study include Ahmad M. Khalil, Mohammad Ali Faghihi, Farzaneh Modarresi, and Shaun P. Brothers of The Scripps Research Institute in Jupiter, Florida.

The study, A Novel RNA Transcript with Antiapoptotic Function is Silenced in Fragile X Syndrome, was supported by Conquer Fragile X Foundation (now part of National Fragile X Foundation) and The Scripps Research Institute Florida. Upon publication, the study will be available at http://www.plosone.org/doi/pone.0001486.

Adapted from materials provided by Scripps Research Institute.

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Blue-eyed Humans Have A Single, Common Ancestor

Daily Science Journal (Jan. 31, 2008) — New research shows that people with blue eyes have a single, common ancestor. A team at the University of Copenhagen have tracked down a genetic mutation which took place 6-10,000 years ago and is the cause of the eye colour of all blue-eyed humans alive on the planet today.

Variation in the colour of the eyes from brown to green can all be explained by the amount of melanin in the iris, but blue-eyed individuals only have a small degree of variation in the amount of melanin in their eyes. (Credit: iStockphoto/Cristian Ardelean)

What is the genetic mutation

“Originally, we all had brown eyes”, said Professor Eiberg from the Department of Cellular and Molecular Medicine. “But a genetic mutation affecting the OCA2 gene in our chromosomes resulted in the creation of a “switch”, which literally “turned off” the ability to produce brown eyes”. The OCA2 gene codes for the so-called P protein, which is involved in the production of melanin, the pigment that gives colour to our hair, eyes and skin. The “switch”, which is located in the gene adjacent to OCA2 does not, however, turn off the gene entirely, but rather limits its action to reducing the production of melanin in the iris – effectively “diluting” brown eyes to blue. The switch’s effect on OCA2 is very specific therefore. If the OCA2 gene had been completely destroyed or turned off, human beings would be without melanin in their hair, eyes or skin colour – a condition known as albinism.

Limited genetic variation

Variation in the colour of the eyes from brown to green can all be explained by the amount of melanin in the iris, but blue-eyed individuals only have a small degree of variation in the amount of melanin in their eyes. “From this we can conclude that all blue-eyed individuals are linked to the same ancestor,” says Professor Eiberg. “They have all inherited the same switch at exactly the same spot in their DNA.” Brown-eyed individuals, by contrast, have considerable individual variation in the area of their DNA that controls melanin production.

Professor Eiberg and his team examined mitochondrial DNA and compared the eye colour of blue-eyed individuals in countries as diverse as Jordan, Denmark and Turkey. His findings are the latest in a decade of genetic research, which began in 1996, when Professor Eiberg first implicated the OCA2 gene as being responsible for eye colour.

Nature shuffles our genes

The mutation of brown eyes to blue represents neither a positive nor a negative mutation. It is one of several mutations such as hair colour, baldness, freckles and beauty spots, which neither increases nor reduces a human’s chance of survival. As Professor Eiberg says, “it simply shows that nature is constantly shuffling the human genome, creating a genetic cocktail of human chromosomes and trying out different changes as it does so.”

Adapted from materials provided by University of Copenhagen.

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Brain Differences Found In People With Migraine ; Scientists Identify Protein That May Promote Migraines

Daily Science Journal (Nov. 19, 2007) — People with migraines have differences in an area of the brain that helps process sensory information, including pain, according to a new study.

The study found that part of the cortex area of the brain is thicker in people with migraine than in people who do not have the neurological disorder.

Comparing 24 people with migraine to 12 people without migraine, the study found that the somatosensory cortex area of the brain was an average of 21 percent thicker in those with migraine.

"Repeated migraine attacks may lead to, or be the result of, these structural changes in the brain," said study author Nouchine Hadjikhani, MD, of The Martinos Center for Biomedical Imaging at Massachusetts General Hospital in Boston. "Most of these people had been suffering from migraines since childhood, so the long-term overstimulation of the sensory fields in the cortex could explain these changes. It's also possible that people who develop migraines are naturally more sensitive to stimulation."

Hadjikhani said the results indicate that the brain's sensory mechanisms are important components in migraine. "This may explain why people with migraines often also have other pain disorders such as back pain, jaw pain, and other sensory problems such as allodynia, where the skin becomes so sensitive that even a gentle breeze can be painful."

Other studies have shown changes in the cortex. The area becomes thinner in neurological disorders such as multiple sclerosis and Alzheimer's disease. But the area thickens with extensive motor training and learning.

This research is published in the November 20, 2007, issue of Neurology®, the medical journal of the American Academy of Neurology.

The study was supported by grants from the National Institutes of Health, the Swiss Heart Foundation, and the Harvard School of Dental Medicine Dean's Award.

Adapted from materials provided by American Academy of Neurology, via EurekAlert!, a service of AAAS.

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Scientists Identify Protein That May Promote Migraines

A University of Iowa study may provide an explanation for why some people get migraine headaches while others do not. The researchers found that too much of a small protein called RAMP1 appears to "turn up the volume" of a nerve cell receptor's response to a neuropeptide thought to cause migraines.

The neuropeptide is called CGRP (calcitonin gene-related peptide) and studies have shown that it plays a key role in migraine headaches. In particular, CGRP levels are elevated in the blood during migraine, and drugs that either reduce the levels of CGRP or block its action significantly reduce the pain of migraine headaches. Also, if CGRP is injected into people who are susceptible to migraines, they get a severe headache or a full migraine.

"We have shown that this RAMP protein is a key regulator for the action of CGRP," said Andrew Russo, Ph.D., UI professor of molecular physiology and biophysics. "Our study suggests that people who get migraines may have higher levels of RAMP1 than people who don't get migraines."

RAMP1 is a normal, required subunit of the CGRP receptor. Russo and his colleagues found that overexpression of RAMP1 protein in nerve cells increased the sensitivity and responsiveness of CGRP receptors to the neuropeptide -- more RAMP1 made CGRP receptors react to much lower concentrations of CGRP than usual and caused the receptors to respond more vigorously to the neuropeptide.

The UI team also engineered mice to express human RAMP1 in their nervous system in addition to the normal mouse version of the protein. These mice had double the amount of inflammation in response to CGRP than did normal mice. Nerve-induced inflammation is one of the effects associated with migraine headache.

Russo explained that his study raises the possibility that people who have migraines may have subtle genetic differences in the RAMP1 gene that result in increased levels of RAMP1 protein.

"There is clearly a genetic difference between people who get migraines and those who do not, and we think that difference could be RAMP1. Our studies provide a reason to look for variations in the DNA that encodes RAMP1 in humans," he said.

The study also suggests that the mice engineered to produce elevated levels of RAMP1 protein may be a good model for studying migraine and specifically trying to understand how the neuropeptide, CGRP, is working.

The UI team investigated CGRP receptors in the trigeminal nerve, which is responsible for relaying almost all sensory perception, including pain and touch, for the front of the head. The UI findings reinforce the emerging view that CGRP receptors in the trigeminal nerve play a key role in migraine headache.

However, there are other CGRP receptors throughout the body, and elevated CGRP levels are implicated in other types of pain, including arthritis. Russo predicts that his group's findings about RAMP1 will have implications for pain research beyond migraine headaches.

The study was funded by the National Institutes of Health and published in the Journal of Neuroscience.

Adapted from materials provided by University of Iowa.

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