Epigenome analysis: Another tool in the personalised medicine kit?

By Laura Blackburn

28 April 2016


It is not only changes to the DNA sequence of our genome that can have an impact on our susceptibility to diseases. There is another layer of control, where temporary changes to DNA - caused by external factors - affect how genes are read and interpreted by our cells, having a potentially profound impact on health. These so-called epigenetic changes point to new tools in the expanding box of prevention, detection and treatment techniques that we could use to tackle disease. But how close are we to realising this potential? 

What is epigenomics?

Epigenetics is the study of the chemical or physical changes to the DNA sequence - or its associated structural proteins - that can modify the activity of the gene by affecting the gene's 'on-off' switch. These changes do not alter the underlying genetic sequence. Epigenetic marks are vital components in the machinery that differentiates all types of cell and tissue in our body, playing an important role in the processes that cause cells with identical genomes to express different sets of proteins and perform radically varying roles in our body.

The same high throughput methods used for genome sequencing - with adaptations - can be applied to achieve genome-wide analysis of the epigenome. Indeed, a number of large scale research initiatives have been undertaken to try and map the landscape of epigenetic regulation in humans, a daunting task given the dynamism of the epigenome and its intrinsic variability within and between individuals.

Analysing the epigenome - What is it good for…?

Changes in the epigenome are induced either by changes to the microenvironment within a cell or macro-scale changes to the whole organism environment such as diet, exposure to chemicals, or physiological stressors, which affect whole tissues and organs. While many epigenetic changes have little impact on gene activity, in some cases they influence susceptibility to and progression of diseases. Variations in the epigenome within and between individuals could therefore, in principle, provide personalised information about disease susceptibility and guide disease management. More controversially, it has been suggested that epigenetic changes can be transmitted to the next generation via sperm and egg cells, influencing susceptibility to certain diseases or other lifestyle factors such as risk of obesity in the next generation. While there is some evidence for this occurring in mice, evidence for the existence of this phenomenon in humans is unclear.

There are two areas where epigenetic information could have an impact on healthcare - as a biomarker to guide decision making, or as a target for disease modifying therapies. While research has shown associations between epigenetic marks and many conditions - e.g. schizophrenia, depression, diabetes, obesity and heart conditions - questions remain about the direction of causality in most of these cases.

Cancer is the only disease area where using epigenetic information has led to clinically useful outcomes. In cancer, certain epigenetic marks correlate with particular subtypes of the disease. While these associations are only correlations (and not necessarily the cause of tumour growth) this information can be used as part of a diagnostic or predictive tests, or to stratify patients into different groups, for example to aid drug choice. Several companies already offer epigenetic diagnostic tests for different cancers, including colorectal, lung and bladder cancers. Some of these tests have received European Regulatory Approval but none are currently used within UK health services.

Pharmaceutical companies are also exploring the potential of therapeutic modification to the epigenome. One drug, Vidaza, is used to treat certain types of leukaemia by blocking methylation of DNA, which restores the cells' ability to control normal growth. A few other cancer drugs have been approved, but the number is small and cancer is the only disease where epigenetic therapies exist. There is great interest in the effect of epigenetic mechanisms on mental health and illnesses, for example, but no therapies have been developed yet. 

What is the future for epigenetics informed healthcare?

Research in epigenetics is vibrant and varied but the complexity of the subject leaves us a long way from translating this research into clinical impact, excepting the examples in cancer described above. 

Converting this research into tests or interventions based on knowledge of the epigenome will, depend on whether we can: 

  • Characterise epigenetic variation in time and space: not only must samples be taken from the correct tissue in order to understand the epigenetic mechanisms of a disease, but also epigenetic biomarkers can appear only at certain time points during disease progression, limiting the window of opportunity for treatment. Some samples may be too difficult or even impossible to collect, for example brain tissue from patients with psychiatric disorders.
  • Understand variation within a sample: clinical samples often contain a varied mixture of cells, which can have different epigenetic profiles, which makes it challenging to identify a typical epigenetic profile of a cell type.
  • Distinguish cause and effect: In some cases, behaviour leads to epigenetic changes, rather than pre-existing epigenetic changes altering disease susceptibility or behaviour. For example, smoking is associated with epigenetic changes, but these changes are caused by smoking rather than the changes making it more likely for these individuals to smoke.

Nevertheless, clinically useful tests and drugs can only be developed through investment in this fundamental research activity, and epigenomics shows sufficient promise to warrant sustained investment in further research. 

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