Over the last several hundred years, we have witnessed marvellous breakthroughs in genetics. From the works of Charles Darwin to Mendel, there is no doubt that these theories have moulded our understanding of genetics today. However a recently emerging area of scientific research could add to our understanding of genes. Epigenetics is an emerging area of medical research of how our behaviour and environment can change the way genes work. Epigenetics cannot alter our DNA sequence, however it can affect how the body reads the DNA sequences.
In the 18th century, the French scientist Lamarack argued that acquired genes can be transmitted. However he believed that this was the sole basis of inheritance which we know is not to be the case. Whereas in Darwin’s theory of evolution, he suggested that lifetime experiences could lead to the formation of gemmules which attached themselves to egg and sperm, hence affecting offspring.
How do epigenetic mechanisms work?
Epigenetic changes affect how genes are expressed. There are various epigenetic mechanisms which can occur in our bodies. DNA methylation and histone modification are examples of these mechanisms.
DNA methylation is the addition of a methyl group to the 5th carbon of cytosine residues( which are linked by a phosphate to a guanine nucleotide ) catalysed by DNA methyltransferases. Consequently this forms 5-methylcytosine. The cytosine residue linked to the nucleotide is known as a CPG dinucleotide. The methyl group is obtained from the methyl donor S -adenosine methionine. Levels of this methyl donor(SAM) depend on the intake of vitamin B12, B6 and folic acid. The methylation of these cytosine residues to form 5-methylcytosine significantly influences cell differentiation. The methylation of CPGs in the promoter region is associated with gene repression. Methylation is known to turn genes ‘off’.
Similar to DNA methylation, histone modification does not alter the DNA sequence however it modifies its availability to the transcriptional machinery. Chromatin consists of histones and DNA. An example of a well known histone modification is the histone acetylation of lysine. Acetylation neutralises the positively charged lysine residue in the histone tail: this reduces the strength of the bond between the DNA and histone tails. This causes it to be more accessible to transcription factors.
Causes behind epigenetic marks
Epigenetic marks can be affected by exposure to various metals. Experimental analyses have shown that there were DNA methylation changes after arsenic exposure.Arsenic can be found in rocks, soil and insecticides. Another metal which is shown to have caused epigenetic alterations is cadmium. Cadmium toxicity mechanisms can cause epigenetic alterations during embryonic development : a set of genes responsible for transcription regulation control have shown changes in DNA methylation associated with concentrations of cadmium in pregnant women. Cadmium can be found in soil, and contaminated water, as well as through diet, for example through cereals, vegetables and smoking.
Furthermore air pollution can affect the epigenome. Exposure to atmospheric pollutants can lead to changes in DNA methylation of immunity and inflammation genes, which has been associated with reduced lung function and thus lung cancer. Benzene is also associated with changes of DNA methylation. Low-level benzene exposure has been linked to blood DNA methylation changes such as a decrease in DNA methylation of the genes LINE-1 and MAGE-1: this could increase the risk of developing acute myelogenous leukaemia.
Diet also can influence epigenetic mechanisms. A reduction in calorie intake might attenuate the epigenetic changes which occur during ageing. Smoking can also result in epigenetic changes. At specific parts of the AHRR gene, smokers typically have less DNA methylation than non-smokers. After a smoker quits, the smoker tends to have increased DNA methylation at this gene.
Epigenetic marks: a cause behind cancer
The first human disease to be linked to epigenetics was cancer. Researchers found the diseased tissue caused by colorectal cancer had less DNA methylation than normal tissue. In normal cells, CpG clusters(known as CpG islands) are normally free of methylation. However, in cancer cells, these CpG islands are excessively methylated, leading to genes turning off that should not be silenced . This typically occurs in the early stages of cancer.
Excess methylation of the promoter of the DNA repair gene MLH1 causes a microsatellite (a repeated sequence of DNA) to become unstable by shortening or increasing its length. This has been linked to many cancers such as gastric, endometrial and colorectal cancers.
At present, two classes of epigenetic drugs have been approved by the FDA, DNA methylation inhibitors and histone deacetylase inhibitors. The first approved drug was 5-azacitidine.
5-azacitidine is an analog of cytidine, with a nitrogen atom in the position of the 5th Carbon. Cytidine can be incorporated into DNA and RNA. Due to 5-azacitidine’s similarity to cytidine, both compounds are recognised by DNA and RNA polymerases, therefore the drug is incorporated into the DNA during replication. The drug is recognised by DNA methyltransferase. The DNA methyltransferase transfers a methyl group as usual. However as the nitrogen is in the fifth position this causes a permanent bond between the DNA methyltransferase and 5-Azacitidine. This causes DNA methyltransferase to degrade, which leads to the reduction in methylation . The drug had a high level of toxicity when tested on mice. Hence the drug is now given in low but repeated doses so the epigenetic effects can occur without a high level of cytotoxicity.
RG108 is a non-nucleoside analog which specifically targets DNA methyltransferases. This interacts with the catalytic domain(the region of an enzyme that interacts with its substrate to cause an enzyme reaction), and then blocks its active site with a low level of cytotoxicity. Unlike nucleoside analogs like 5-Azacitidine, non-nucleoside analogs do not incorporate themselves into DNA. Therefore they do not induce any toxicity.
In conclusion, epigenetics has significantly added to our understanding of how environmental influences can affect whether and how genes are expressed. Epigenetics drugs have a great potential to be effective against a number of cancers by reversing epigenetic mechanisms. The field of epigenetics will continue to grow, enabling scientists to develop more targeted drugs against cancers.
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