What is Epigenetics and the Epigenome?
The objective of this paper is to outline and discuss difference between an actual change in the genetic sequence of our DNA versus an epigenetic modification. The paper will discuss ways in which genetic changes and epigenetic modifications can influence an individual or an entire population. Genomic sequences change over a long period of time through environmental factors. These genetic changes may spur a phenotypic response in the organism that is largely irreversible or permanent unless another environmental factor applied over a longer period causes an overriding mutation.
More recently, epigenetics has suggested that aside from mutations to DNA, an organism and several generations of its offspring can be influenced temporarily by modifications to the DNA strands such as methylation and histone modifications. This new field of genetics gives rise to a topic much more complex than the originally known genome: the epigenome. The article discusses how genetics and epigenetics are related as well as how the epigenome can explain certain diseases in humans.
Introduction to the Epigenome
Epigenetics was first recorded in literature in the 19th century however the concept has been known to date back to Aristotle’s time (McVittie 2006). Epigenetics is a change that occurs in the genome that is not due to a change in the genetic sequence of DNA but rather by genes being turned on and off for a shorter period of time. It has been suggested that these changes in the epigenome are heritable over a few generations, and can be undone once previous environmental conditions are restored (Pembrey 1996).The four most common types of epigenetic marks include methylation, histone modification, nucleosome remodeling, and non-coding RNA-mediated pathways, although the ones most commonly studied are histone modification and the methylation of DNA (Ridley 131). These marks come together to create the epigenome, which is estimated to be 50-100 times as large as the human genome. For reference, the human genome contains around 25,000 genes and it took three billion dollars to map them all (Cloud 2010).The epigenome can explain to us why identical twins can develop different diseases even if they are exposed to the same environmental conditions. It is almost like a second genome that is attached to the first one and it may provide the answers that simple genetics cannot. Until recently it was believed that our DNA was the written code that determined our destiny but the epigenome is bringing nature and nurture together. We are beginning to understand how choices we make can change our genes and even those of our children.
Significance of the Epigenome
So what is the point of having an epigenome if a complex enough genome exists? Dr. Anne Brunet, a geneticist at Stanford University, conducted a study in 2011 on chromatin modifiers of Caenorhabditis elegans, nematodes, which were exposed to the same environmental conditions to study the effect on lifespan. To produce these results the nematodes with genetic deficits in life span were crossed with the wild type nematode to yield both wild type and genetically deficient nematodes. These two types of offspring were then compared with the control populations, wild type offspring from wild type parents. The wild type offspring that was descended from the nematodes with genetic deficiencies lived 20-30% longer than the control population and their offspring had longer lives as well for up to three generations, after which the longevity effect seemingly wore off (Brunet 2011). The genetic deficits were not inherited so Brunet and her team came to the conclusion of methylation. The genes themselves were not altered because each subsequent generation was genotyped. However, the methylation was an epigenomic mark that allowed one type of offspring to survive longer than another and to pass that mark down for three generations. The study suggests that perhaps it is better if we have an epigenome that can temporary control the genome. Matt Ridley, states that we have certain genes in our body that are there only because they are productive at replicating themselves, such as the gene which supports the AIDS virus. The gene is always there but fortunately we have epigenetic marks that allow the gene to be methylated and therefore be inactive (130). In the beginning of his chapter Chromosome Eight on Self-interest he quotes Richard Dawkins, from his book The Selfish Gene. Dawkins states that our bodies are just a vessel to preserve “selfish molecules” which are our genes. The discovery of the epigenome challenges this idea and forces us to rethink about how much control genes have over us.
How DNA Methylation Occurs
Considering Lamarck’s Evolution Hypothesis
Jean-Baptiste Lamarck, had a theory that evolution could occur within a very short amount of time, a generation or two. According to epigenetics, he might have been right. Though in 1809, when his thesis was published, his conclusions were considered a scientific mistake (Cloud 2010). A famous example that supported Lamarck’s evolution was that giraffes grew longer necks because their recent ancestors had to stretch more to reach leaves in trees that were too tall. Darwin, in contrast, argued that the giraffes gained this ability over thousands of years. Essentially, one theory implied mutations in DNA, which happen over a long period of time, and the other implied modifications to the epigenome, which gave those giraffes a quick boost so that the population could reach those trees which had grown particularly tall (Urry et al. 2011).It turns out there is a good purpose to the epigenome, survival. Perhaps those giraffes and their offspring would have starved if there was no epigenetic mark for the long necks to be inherited.
The Influence of the Environment on the Epigenome
More recently, Lamarck is not the only one to conduct studies on how food sources affect populations. In 2007 Dr. Lars Olov Bygren, a preventative-health specialist at the Karolinska Institute in Stockholm, and his team conducted a study on how food availability from 1800-1863 in the isolated Norrbotten, Sweden affected the population and several generations after during times of abundance and scarcity. The results he came across were published in The European Journal of Human Genetics and the study received its own cover in the January 2010 TIMES magazine. Bygren went through the agricultural records of 99 random individuals in Norrbotten and determined how much food had been available to the parents and grandparents of those individuals during those 60 years. He found that the parents and grandparents who endured a severe starvation had a genetic mark imprinted on their genetic material which passed along new traits to the generation directly after. The results he came across were that the parents and grandparents who almost starved, produced offspring that lived an average of six years longer than the offspring of the parents and grandparents who had plenty of food during the harvest.The TIMES publication states that once social and economic controls were tested for in Bygren’s study, the difference in life-span for the individuals with parents and grandparents exposed to the famine increased from six years, to a startling 32 years. The stressor, which in this case was abundant food, activated or deactivated an epigenetic mark and this was immediately passed down to the next generation. This way if the next generation also had to endure starvation, they would have a better chance at surviving and reproducing if they had the advantage of a longer life-span. The epigenome is like a shortcut of evolution, or in Bygren’s study literally a hack for either a shorter or longer life.
Just as the mapping of the genome led to an understanding about how genes work, how medicines can be developed to deal with disorders, and why all this diversity exists, the discovery of the epigenome must serve some useful purpose also, otherwise why continue studying it. The way the epigenome interacts with the genome is useful in understanding things such as drug interactions and human diseases like cancer. A study published in the Journal of Biotechnology suggests that certain epigenetic changes can be permanent and are responsible for how susceptible an individual is to certain diseases and also how susceptible the next generation is (Li et al. 2012). This study proposed the advancement of DNA vaccines using epigenetics as a guiding tool to design the vaccines, and understand the mechanisms by which they work.A complementary experiment in the Journal of Gene Medicine tested what happened when rats were given a vaccine of a first-generation Ad containing the human fibroblast growth factor 4 (hFGF-4) gene driven by the cytomegalovirus (CMV) promoter and enhancer (CMV-PE). The results were measured for 84 days after the injection and the methylation status of the CMV-PE DNA was determined. The conclusions the experiment reached support the theory that the epigenome can help us understand how some disease are caused. The study found that extensive methylation of the CMV-PE enhancer quickly decreased transcription, within 24 hours. The mice that had the injection but also had the DNA methylated did not grow (Brooks et al. 2004). A study like this can show how an epigenetic mark can be used to silence a mutation in the DNA. If it was a harmful mutation we could develop vaccines that targeted these disease-causing genes and either methylated or demethylated them according to the disease we want to rid ourselves of. Ridley states that methylation might be involved with suppressing transposons and other intragenomic parasites (130). Therefore if something goes wrong and a promoter that is supposed to be methylated and silenced suddenly becomes active, then a vaccine that targets that promoter and methylates it would be the perfect cure (Brooks et al. 2004).
Some media magic to put the science in plain language
The Future of Epigenetics
A good example of demethylation is in cancer tumors. Ridley states that one of the first things to happen in cancer tumors is a demethylation of the genes. These promoters then become active and start transcribing the DNA that is filled with oncogenes. Even worse, these oncogenes are transposons, which mean they can be integrated at different places in the chromosome, and therefore make the cancer worse (131). A gene that causes cancer and other genes that have been integrated into our DNA over our past generations are already implanted into our genome, but the epigenome keeps them silenced. For example, the UHRF1 gene is significantly over expressed in various cancers as the DNA tries, and fails to repair itself in the cancer cells (Unkoi 2009). The UHRF1 gene contributes to keeping certain parts of the DNA methylated. If the maintenance is disrupted various genes start to become expressed and disturb the cell, potentially causing it to become cancerous. If UHRF1 is the gene that interferes with cancer cell proliferation, then in theory a vaccine could be made to epigenetically change that gene and make it more effective at methylation and suppressing the cancer cells. Suddenly the idea that our genome holds our destiny may not exactly always be true. Methylation, an epigenetic mark, can diminish the role of this selfish gene.
Epigenetics is challenging traditional ideas about the DNA code dictating a fate. It is true that the genome is our genetic code for functioning but epigenetics is taking a different stand in nature versus nurture and making us reevaluate Lamarck’s theory of this short term evolution. Bygren and his colleagues demonstrated that epigenetic makes can be passed down in a very short amount of time, and Brunet’s research also supports this idea. This is great news is that there is always more to discover. The epigenomic contributions to medicine already show what an important discovery epigenetic marks are. Scientists can use these marks to switch off genes that lead to cancer, blood disorders and numerous other diseases. This task becomes easier than trying to mutate the actual DNA code in each and every cell in hopes of stopping a disease. The future of epigenetics looks promising as we learn how the epigenome affects the genome and the ways we can now manipulate our genes through a fast-paced evolution.
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