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  • Hugo Creeth

The Epigenetic Epiphany

Updated: Feb 17, 2018

The Genetic Discovery: DNA


Many believe that Watson and Crick were the scientists who discovered DNA in the 1950's, however they would be wrong...


In 1869 a Swiss physiological chemist, Friedrich Miescher, discovered a substance he termed “Nuclein” inside human white blood cells. This substance nuclein is what is known today as DNA. This was the perhaps one of the biggest, yet most over looked discoveries by one man in science. It wasn't until a Russian biochemist Phoebus Levene, who was first to discover the phospate-sugar-base backbone of DNA and its carbohydrate component, and later Erwin Chargaff that DNA became well known. It was the combination of these three names research that laid the foundation for Watson and Crick's landmark discovery of the double helical structure of DNA in 1953.


Genes are essentially packets of information that are coded by a series of bases (adenine, cytosine, thymine and guanine). These form sequences that are transcribed and translated into proteins that perform the necessary functions for life. It was the 1950's era that saw a broad range of principles published that defined the methods by which DNA, or the blueprint for life was inherited from generation to generation. These principles forged around Mendelian genetics, despite being extremely accurate, did't explain all inheritance.


A Silent Beginning


From maize seed coloration to sex chromosomes in mammals. The early signs for the existence of the epigenetic field began with the identification of various forms of gene/chromosome silencing.


The mammalian sexes are defined as males having one X and one Y chromosome, whilst the females have two X chromosomes. These sex chromosomes or gonosomes are the 23rd pair of chromosomes in human beings. They are expressed in each cell, however in order to only express one X chromosome in females and avoid a double dosage effect, one of these X chromosomes is selected at random in the embryonic stages of development and inactivated. This X chromosome inactivation is then constantly passed through all future cell divisions during fetal development and growth.


Imprinting is another type of gene silencing that offered the first clues to the existence of the epigenetic phenomenon. Imprinting was discovered a few years after X chromosome inactivation. Each gene in the human body is present in two copies (alleles), each from a different parent. These alleles, however, may behave differently depending on which parent they come from. The major example for this type of gene silencing is the IGF2 gene that codes for the signalling molecule known by the same name IGF2 or insulin-like growth factor 2. IGF2 promotes fetal growth during gestation, and the copy inherited from the father is permanently switched on whilst the copy from the mother is permanently switched off.

There are now thought to be over 80 imprinted genes in humans and 100 in mice. The majority of these genes seem to be involved in embryonic development and growth, which helps explain their existence. From an evolutionary standpoint, it is more beneficial for fathers to have larger babies and vice versa. The question remained however, how could the genes realise which parent each allele was inherited from? As time passed and knowledge grew the two phenomena that have just been outlined were hypothesised to perhaps belong to a pattern of inheritance that didn't involve genetic changes to the DNA itself but something else. Something controlling the expression of the DNA itself and so “Epi-genetics” was born.


The Processes


The processes and mechanisms involved in the epigenetic phenomena unravelled themselves soon after the identification of X chromosome inactivation and imprinting. They primarily involve either chemical changes to the DNA or the proteins that package the DNA, promoting or suppressing the gene or genes expression.


DNA Methylation


Methylation of the DNA is the first means by which epigenetics was shown to work. DNA methylation acts by adding a small methyl subunit to DNA. Methylated cytosine has long been known as DNA's fifth base, however with the ability to map the location of this base appearing in the 1970's it became evident that this supposedly random member of the genetic code was conspicuously absent from gene control regions. This is vital as critically for DNA methylation, whenever the control region is methylated, the gene is silenced and cannot be switched on.


Histone Modification


Histones are the associated proteins of DNA. They help package DNA in all complex organisms, including plants, fungi and animals. They work by having the DNA wrap around them in a long row, often said to resemble beads on a string. The proteins themselves vitally have long molecular tails that allow for chemical modifications.


Much like DNA histones can have methyl subunits added to their molecular tails, however they are also able to undergo many more chemical modifications. These range from the addition of phosphate groups, acetyl groups and other proteins. Unlike methylation of DNA, the methylation of histones can result in either the silencing or the enhancement of genes dependent on where the methyl group binds on the histones tail. Similarly by distinct contrast histone acetylation has the effect of always switching genes on.

There are thought to be over 50 types of potential chemical modifications to the histones that are used to induce various expression changes on the genes of an organism. The majority of which are still not well understood.





The Mechanisms


The way in which these processes exert there changes on the genome of an organism are mediated by a three distinct classes of proteins, much like the enzymes that translate and transcribe DNA into mRNA. These three classes are:

  • Writers: these are a group of enzymes that actively add chemical modifications/marks to the DNA and Histones.

  • Erasers: as the name suggests it is these enzymes that actively remove such marks made by the writers.

  • Readers: are the enzymes that interpret or “read” the marks added or removed by the former two classes add either cause the gene to be silenced or activated based on the specific marks added.

Each epigenetic mark out of the 50 that have been discovered are thought to possess their own unique set of writers, erasers and readers. Making the understanding of each mechanism complex and in many ways daunting for those scientists working in the field of epigenetics.


Epigenetic Research


The influence of epigenetics on the human condition and consequently its role in human disease is an expanding field of research. Changes to the epigenome have already been linked to several congenital diseases and also implemented in the development of certain cancers. Perhaps the most controversial area of research is the idea that the environment can influence the way our genes are expressed and thus ultimately our bodies and our behaviour could, after all, be a result of the world we are brought up in and not just our genetic code. So reigniting the nature vs nurture debate once again...


Disease


Congenital disorders are ones that exist at birth and commonly begin before birth. They have a variety of origins and are often described as idiopathic. Epigenetics has offered a new explanation for several disorders that have previously not had causes that have been well understood. An example of a potentially purely epigenetic disease is Beckwith-Weidemann syndrome (BWS). A disease that causes fetal overgrowth and can lead too tumours in childhood and disfigurements, has been shown to be linked too the inadequate silencing of the maternal IGF2 allele. Silver-Russell syndrome (SRS) is another such case, conversely to BWS, SRS is a syndrome that results in one of 200 types of dwarfism, including primordial dwarfism. It also involves epigenetic changes in IGF2, but also in the H19 gene that is maternally expressed and paternally silenced. In both cases hypo-methylation of these genes is a major cause of the fetal growth restriction seen in SRS.


The occurrence of both BWS and SRS are thought to increase in likelihood were assisted reproductive technologies are used, such as IVF. Something that is also seen in Prader-Willi syndrome and Angelman syndrome, two other congenital disorders associated with imprinting changes. The reasoning behind this therefore points to a critical period during early development that is key for the laying of the correct epigenetic marks, which if disturbed can have dramatic developmental repercussions.


Cancer


Cancer is one of the biggest killers in the UK and across the western world. It occurs when cells don't follow the usual cell cycle constraints that eventually result in programmed cell death (PCD). Cancer cells are able to proliferate and produce multiple daughter cells which ultimately contribute to form cancerous tumours. The majority of evidence points towards genetic mutations as the main factor in cancer, however there is mounting evidence that there may also be considerable epigenetic elements to the disease.


Two genes implemented in two types of cancer have been demonstrated to have significant epigenetic factors governing their role in the cancerous cells. MLH1 is commonly mutated in colon cancer. Its protein product is vital for mopping up damaged DNA in the cell. Studies have shown that in several cases MLH1 is silenced via DNA methylation. Similarly TET2 is often mutated in myeloid cancers (red blood cells). The role of TET2 is to remove a methyl group on DNA at certain points during the cell cycle in order to stop inappropriate gene silencing. It does this by converting the target methyl group into a hydroxymethyl group, which is easily removed. When TET2 is missing or mutated methylation of DNA at these critical sites rises resulting in unwanted gene silencing and cancer.


The most exciting side of cancer epigenetics is the invention and circulation of new drug treatments that themselves offer the best evidence for an epigenetic element or perhaps weak spot in many cancers. Demethylating drugs, for example decitabine is now used with great success to treat leukemias. Deacetylase inhibitors, namely Vorinostat, are used to treat some lymphomas by stopping the “erasing” of the acetyl groups from histones. The danger of causing system wide changes in epigenetic marks has also been shown to be exceptionally low, as the concentrations needed to kill cancer cells is relatively non-toxic to ordinary cells. Something that is extremely positive for the future progress of anti-cancer medicine.


The Environment


The most commonly asked question regarding epigenetics is whether the environment can impact upon the expression of certain genes. The evidence is not conclusive in the absolute sense. This is because most epigenetic mechanisms respond to changes that occur internally within an organism, including X chromosome inactivation and genomic imprinting that occur during embryonic development and our time in the womb.


Even so, some evidence does exist, in particular on the way in which diet can be found to influence DNA methylation. The most common example of this occurrence is in the agouti mouse. Agouti mice are mice with an array of different coat colours. Usually one litter has coat colours ranging from yellow through brown to almost black. This spectrum of colours is a result of the agouti gene. Research into these animals should that when these mothers where fed a diet rich in vitamins and amino acids containing methyl groups the litter of pups contained significantly more with a light brown coat. This is a direct consequence of the agouti genes high sensitivity to methylation. The presence of a transposon seems to be to blame for the agouti genes hypersensitivity to methylation. When low there are more yellow mice and vice versa.


Does this translate to the human setting? Studies in human pregnancy upon maternal diet and stress have been shown to have long term impacts upon the health outcomes of the offspring, perhaps the most well known being that children of malnourished mothers have a higher risk of heart disease and diabetes. The epigenetic evidence, as already mentioned is inconclusive at this time, although many theories regarding evolutionary adaptive strategies have been proposed which make sense, if epigenetics is a factor.

There are of course many other examples of potential environmental impact upon offspring, one study in rats showed that maternal neglect resulted in skittish young that persisted into adulthood via DNA methylation upon a gene that regulates the stress response in this species. Similar studies in humans are to under powered at present to draw meaningful conclusions. But the principles are there and with more work may become more valid.


One more thing...


An area that hasn't been touched on in this article is the debate about epigenetic inheritance and transgenerational effects of epigenetic changes upon future generations. It focuses on the concept that epigenetic marks acquired through an individuals life can be learned and passed through the germ line. However there is little in the way to support such a view at present and therefore is a vary open field of discussion.


Epi-logue


Epigenetics has become a fashionable facet of science and society alike. Its plethora of possible uses, ranging from anti-cancer drugs to understanding how the environment can influence our children and ourselves, has meant that it itself is often misunderstood. Many believe that it replaces the outdated idea that humans and organisms in general are programmed by their genes, with a more exciting paradigm that opens new windows for research. Others are more cautious, and rightly so, highlighting the promise of epigenetics in biomedical research and scientific knowledge of diseases, but emphasising that rather than replacing genetics it simply adds to it, rather than epigenetic mechanisms becoming the sole means that genes are switched on and off, they combine with the status quo and reinforce it. Epigenetics is a young phenomena one that will undoubtedly unravel many more discoveries in the years to come. So as the quest to map the epigenome takes off it is safe to say far from being the epilogue of the epigenetic story this is just the introduction.


References


Perceptions of epigenetics A. Bird Nature 447 396-8  (2007)

Epigenetics: what is it and why is it important to mental disease? A. R. Isles and L. S. Wilkinson Br Med Bull 85 35-45  (2008)

Epigenetic mechanisms in the pathogenesis of Lynch syndrome P. Peltomäki Clin Genet 85 403-12  (2014)

TET2 Promoter DNA Methylation and Expression Analysis in Pediatric B-cell Acute Lymphoblastic Leukemia E. Musialik and M. Bujko and A. Wypych and M. Matysiak and J. A. Siedlecki Hematol Rep 6 5333  (2014)

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