Epigenetics and Disease Susceptibility

                  Randy Jirtle (right), a professor of radiation oncology at Duke university, has worked with Michael K.Skinner, a geneticist at Washington State University, on the study of epigenetics’ influence on disease susceptibility. Epigenetics, or literally translated as “on”genes, refers to the modifications, mitotically or meiotically, in the gene expression which are heritable, but do not involve a change in DNA sequence. This is not similar to genetic mutation because epigenetic changes are likely to be reversible. Since genes carry ‘blueprints’ to the production of proteins in cells, DNA sequence can be further transcribed into RNA, which is then translated into proteins. Epigenetic modification works by turning “on” or “off” the genes, which allows or prevents the genes from being available to make certain proteins. Some common forms of epigenetic changes are through DNA methylation and histone modifications. During DNA methylation, an additional methyl group (a carbon atom plus three hydrogen atoms) is being added to specific bases on the DNA sequence. This intervenes with the chemical signals that would order the gene into action and therefore silences the genes. However, in histone modification, it involves the fact that DNA is wound around proteins known as histones and is unwounded to be transcribed, therefore, alterations to the histone orientation (DNA packaging) causes some genes to be more or less active to the cell’s chemical process and thus effects the gene expression in a similar fashion as in DNA methylation


In the study of epigenetics by Jirtle and Skinner, it is suggested that environmental exposure early in development have a role in susceptibility to disease later in life which seem to be passed on through successive generations. The study is supported by using the evidence from animal studies which indicates that prenatal and early postnatal environmental factors—including nutritional additions, xenobiotic chemicals, behvaiourial cues, reproductive factors, and low-dose radiation—can result in altered epigenetic programming and the risk of developing disease. Agouti mice, which are characterized as fat and yellow, were used in the experiment since they carried the agouti gene which makes them prone to cancer and diabetes. When agouti mice breed, a typical result is that they are identical to their parents (yellow, fat, and susceptible to life-shortening disease.) However, in this experiment, an offspring with alternated looks were produced (brown, slender, and lived till old age). In addition, the parents’ susceptibility to cancer and diabetes were eliminated.

The mother agoutic mouse (right)  has given birth to the young mouse that has completely different appearance and  disease susceptibility

The approach that the researches had taken did not involve any alternation of a single letter of the agouti mice’s DNA but rather, they changed the maternal dietary. The coat color is primarily yellow in the offspring that are born to unsupplemented mothers, whereas it is mainly brown in offspring from mothers that were supplemented with methyl-donating compounds (picture below). Before conception, the mother mice were fed with a diet rich in methy donors that is, folic acid, choline, vitamin B12, and betaine (common in onions, garlic, beets, and in the food supplements often given to pregnant women), which are small chemical clusters with the ability to attach to a gene and turn it off. The way this chemical works after being consumed by the mother is that, it attaches onto the developing embryos’ chromosomes and the critical agouti gene. As a result, the agouti gene is still passed on to the offsprings, but due to the methy-rich pregnancy diet, the gene acts as a chemical switch that diminishes or inhibits the gene’s deadly effects. Methylation-sensitive restriction-enzyme analysis followed by PCR amplication have been used to identify the set of genes and other DNA sequences with altered DNA methylation that is epigenetically reprogrammed.

a. Group of mice with dietary supplementation of methyl donating substances to female mice during pregnancy vs. the group without dietary supplementation./ b. The effects of maternal dietary supplementation on coat colour distribution. The coat colour is primarily yellow in the offspring that are born to unsupplemented mothers, whereas it is mainly brown in the offspring from mothers that were supplemented with methyl donating substances.

Furthermore, epigenetics involves transgenerational inheritance in which is the transmission of a biological trait to successive generations through the germ line and in this case, without changing a single gene sequence. Michael skinner proved this to be true in 2004 after he discovered an epigenetic modification in rats that lasts for at least four generations. Another study done by biologist Emma Whitelaw in 1999 (using mammals) also supports that epigenetic marks could be passed through to subsequent generations. Another research conducted by the research team in Linköping University in Sweden also reaches an analogous conclusion by using chickens (shows eight generations of epigenetic marks). At the moment, evidence is only enough to be done with animals, but there are still gradual evidence that epigenetic modifications might work in humans as well. 


 In conclusion, the study done by Jirtle and Skinner has highlighted the indication that environmental factors are able to alter gene expression and change phenotype by modifying the epigenome. Moreover, if these environmentally induced epigenetic adaptations occur at crucial stage of life, they can potentially change behavior, disease susceptibility and increase possible chances of survival. They can be used as therapeutic approach for early diagnosis of individuals with a tendency for adult-onset disease. 


 "Epigenetics is proving we have some responsibility for the integrity of our genome," Jirtle says. "Before, genes predetermined outcomes. Now everything we do—everything we eat or smoke—can affect our gene expression and that of future generations. Epigenetics introduces the concept of free will into our idea of genetics."


MLA:
 1. Downer, Joanna. "Backgrounder: Epigenetics and Imprinted Genes." Johns Hopkins Medicine, Based in Baltimore, Maryland. Web. 29 Apr. 2012. . 
 2. Watters, Ethan. "Living World / Genetics." DNA Is Not Destiny. Nov. 2006. Web. 29 Apr. 2012. 
 3. "Inherited Epigenetics Produced Record Fast Evolution." ScienceDaily. ScienceDaily, 29 Feb. 2012. Web. 29 Apr. 2012. . 
 4. PDF file: http://www.geneimprint.com/media/pdfs/17363974_fulltext.pdf