Epigenetics and its Potential Uses in Treatments

 by Saanvi Ganesh

Ever since Watson and Crick proposed the double-helix model for DNA in 1953, it has been taken as a fact that DNA acts as the blueprint for cell function. This model excluded environmental influence on phenotype, for example the level of nutrition available to a foetus in its first trimester of gestation influences the baby's birth weight. It is now accepted that while genes determine the features of an organism, the environment can influence the expression of these genes through modifications and there is now evidence that these modifications can be passed onto offspring without changing the base sequence of DNA. This is even causing scientists to revisit previously discredited theories of evolution suggesting that acquired characteristics could be passed onto offspring (Lamarckism). These modifications are known as epigenetics.

DNA is wrapped around proteins called histones which are covered in chemicals called tags. These tags make up a second layer known as the epigenome. The epigenome is flexible and tags can be removed and added in response to the environment or during cell differentiation in early development. The epigenome determines the shape of the DNA-histone complex: genes are tightly packed around histones to ensure that they cannot be read by transcription enzymes (they are switched off and is known as epigenetic silencing) and genes are loosely associated with proteins so they are easy to read when they are switched on. The epigenome can determine the degree to which genes are switched on and off (or how tightly they are associated with histones). This is known as gene expression.

Epigenetic modification takes place through two possible mechanisms that are currently known and agreed upon. These are acetylation, which increases gene expression and methylation, which decreases gene expression. Acetylation is the process whereby an acetyl group is transferred to a molecule; in this case an acetyl group is transferred from an acetylcoenzyme A molecule to a histone. It removes the positive charge on histones, decreasing the interaction between the N termini of histones with the negatively charged phosphate groups of DNA. So increased acetylation leads to DNA being loosely associated with histones, which means these genes have increased expression. Methylation is the addition of a methyl group to a molecule; in this case a methyl group is added to the cytosine bases of DNA. Methylation inhibits transcription of genes by two methods: preventing the binding of transcriptional factors to DNA and attracting proteins to condense the DNA-histone complex. The latter is done by inducing deacetylation of histones.

The environment affects gene expression through stimuli which produce a response within the organism, which can lead to alterations in gene expression. For example, in a stressful situation, the hypothalamic-pituitary-adrenal axis or HPA axis produce glucocorticoids like cortisol, which is a stress hormone. A previous study in mouse models where a group of mice were given drinking water with added corticosterone (a stress hormone produced by mice in stressful situations) for 4 weeks with a recovery period of equal length. The mice were then tested in stressful situations for behavioural and physiological changes and the expression levels of 5 HPA axis genes were examined along with the genes’ methylation levels. The researchers reported that mice who were given corticosterone appeared more anxious during maze tests and that chronic corticosterone exposure led to decreased methylation levels in the Fkbp5 gene (this gene codes for a protein that interacts with the glucocorticoid receptor in the HPA axis). They also reported altered expression of 2 other HPA axis genes that were tested.

Many diseases are known to have a genetic component, but the epigenetic components are still yet to be discovered. A number of diseases are known to change the expressions of genes within the body, with epigenetic modification as a plausible hypothesis for their method. These changes may also be the symptoms of the disease. Cancer is one of the main diseases suspected of altering gene expression, resulting in alterations to the cell cycle and its usual checkpoints.

Traumatic experiences can lead to many problems, including PTSD, which is treated by cognitive behavioural therapy (CBT) methods like exposure therapy. In exposure therapy, patients are exposed to fear and anxiety-inducing in a safe and controlled environment. This method eventually leads to a decreased association between the stimulus and fear or anxiety. The biochemical mechanisms that explain why exposure therapy works are not yet fully understood, however successful exposure therapy has been linked to increased acetylation of two genes (BDNF and NMDA). This leads to activation of these genes which in turn increases neural plasticity. Because of this, recent research has involved the increase in acetylation of these two genes in the treatment of anxiety disorders. Rodent models have found a number of drugs effective, two of which have shown effectiveness in human trials (Vorinostat and Entinostat). It is hypothesized that exposure therapy works through a learning mechanism, which can be enhanced by drugs and treatments that induce neural plasticity. However, this learning can also be re-consolidated if exposure therapy is unsuccessful.

A number of cardiac dysfunctions are associated with cytosine base methylation patterns. For example, atherosclerosis tissue has increased methylation in the promoter region for oestrogen, although a link between the two is unknown. Hypermethylation of the gene that catalyses conversions between cortisone and cortisol is correlated with hypertension. The mechanisms for these are highly speculative and are an area of future research. Treatment methods are also highly speculative and the primary area of research is methods to increase cardiac tissue regeneration after damage from disease.

Epigenetic roles in cancer have been studied intensely with a key finding regarding epigenetic therapy. These are that cancers use epigenetic modification mechanisms to deactivate cellular antitumor systems. Treatments have been developed to reactivate the systems silenced by the cancer. For example, Zebularine, an activator of a demethylation enzyme has been used with some success. However, these medications have major side effects because of their wide-ranging effect on the entire organism. But survival rates increase significantly when they are used for treatment.