Shankar Balasubramanian Ph.D. Molecular Scientist and Co-Founder Cambridge Epigenetix.

A New Perspective for Genomic Research from Prof. Shankar Balsubramanian

Epigenetic research and our growing understanding of dynamic DNA remodelling have brought a completely distinct dimension to the study of genetics and genomics in recent years. These insights have enabled the scientific and medical community to view human health and the pathogenesis of disease from a fresh perspective, inspiring a new generation of technologies and innovations with the potential to revolutionize diagnostics and therapeutics.

The discovery of the DNA modification 5-hydroxymethylcystosine (5hmC) in 2009 was the defining moment that first ignited my interest in this fascinating and important field of research. This led our laboratory to develop oxidative bisulfite sequencing (oxBS-Seq) (now known as TrueMethyl©): the first technology to enable the accurate quantification and single-nucleotide mapping of both 5-methylcystosine (5mC) and 5hmC. This technology, used for analyzing nucleotide methylation, was also the founding vision for Cambridge Epigenetix.

Since then we have made many advances, including the identification and mapping of another distinct methylation variant, 5-formylcytosine (5fC), during early mammalian development (in collaboration with Wolf Reik, M.D., at the Babraham Institute, Cambridge, U.K.). We have demonstrated that 5fC, 5mC, and 5hmC alter the physical properties of DNA and form stable structures that can not only be measured but, importantly, mapped to precise genomic locations. This is a hugely exciting area of science that has significantly advanced our understanding of the roles that DNA modifications play in human development, aging, and health.

Personalized Medicine

There is an increasing global emphasis on personalized medicine, focusing on genetic factors associated with disease, particularly in the treatment of cancer and rare disorders. Alterations in levels and patterns of 5mC and 5hmC methylation are becoming central to much of this research. It is wonderful to see the field develop and to know that we initiated the technology at the heart of this valuable research.

Epigenetic modifications are stable, rather than intermediary, suggesting a significant purpose in disease onset and progression. Drugs are already in use that target epigenetic machinery, predominantly in the field of oncology, and a growing body of evidence also supports the use of these modifications as biomarkers for disease diagnosis, prognosis, and monitoring.

On this topic, our recent paper (published in Genomic Medicine) examines 5hmC modifications within glioblastoma tumor cells. We have identified that neighboring non-tumor cells display epigenetic alterations characteristic of the tumor itself, although they appear genetically “normal” (Raiber, 2017). These findings support the use of epigenetic-based biomarkers in detecting early-stage tumorigenesis, before any genetic changes have taken place.

Johnson et al. (2016) also highlighted the promise of 5hmC as a marker for diagnosis and an indicator of disease progression in people with glioblastoma, demonstrating that changes in levels of 5hmC regulate transcription of disease-critical genes in specific tissues. Global reduction in 5hmC across the genome is associated with poor clinical outcomes in these patients (Johnson, 2016). In addition, lung and liver cancer research suggests that both 5mC and 5hmC play significant roles in the regulation of gene expression and active histone modification during development of malignant disease (Li, 2016). These results are in line with our recent findings and highlight potential for epigenetic approaches within this rapidly evolving therapeutic area.

Alterations in DNA methylation and hydroxymethylation are also considered key regulatory elements associated with neurological aging. Neuroepigenetic research has improved global understanding regarding the aetiology and pathogenesis of neurodegenerative disorders. For example, changes in 5hmC and 5mC levels correlate with pathophysiological indicators of Alzheimer’s disease (AD) (e.g., amyloid plaques, neurofibrillary tangles) (Chouliaras, 2013; iTero, 2017). It is believed that environmental factors may influence epigenetic modifications, leading to development of AD and other neurogenerative conditions (Chouliaras, 2013; Iatrou, 2017).

Identification of these fundamental epigenetic modifications and markers may allow health disorders to be recognized at earlier stages in development, before diseases have progressed and symptoms have worsened, improving treatment outcomes and quality of life for many people.

Liquid Biopsy

Liquid biopsy (LQB) is unlocking possibilities for early detection of cancers and other diseases, with significant potential for treatment enhancements and prediction of prognosis in clinical practice. Modern genetic analysis techniques allow genomic DNA fragments to be extracted and examined from circulating plasma. Cambridge Epigenetix has combined the latest advances in LQB with its epigenetics expertise to develop proprietary tools that enable precise detection of epigenetic biomarkers from cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA). Using these highly sensitive techniques, exceptionally low concentrations of cfDNA (< 10ng/mL) can be analyzed from circulating plasma samples to identify critical changes within the epigenome before genetic modifications have taken place.

Companies such as Cambridge Epigenetix are playing a key role in broadening clinical and scientific access to these leading-edge innovations through both in-house biomarker development programs and collaborations with biopharma partners. The potential of these technologies in advancing our understanding and improving management of human health is vast, but conceptually incredibly exciting.

Our understanding of the epigenome has developed exceptionally rapidly over the past 10 years, with nucleic acid modifications now known to be established elements in the biological pathways that influence human development, health, aging and disease.

Technological advances bring new possibilities and opportunities for our epigenetic knowledge to be translated into practical tools and systems that improve recognition and treatment of disease, as well as outcomes for many people living with life-threatening conditions.

Epigenetic innovations are inspiring the latest point-of-care diagnostics and the next generation of therapeutics. In the future, these tools may facilitate ongoing monitoring of the epigenome and recognition of disease onset at the earliest of stages, even before genetic changes have occurred. Perhaps these advances may help to shape our approach to the management of human health and well-being, enabling truly personalized healthcare to finally become a reality.

Professor Sir Shankar Balasubramanian,  Ph.D., FRS, ([email protected]), is a molecular scientist and co-founder of Cambridge Epigenetix.



Chouliarasa L, Mastroenia D, Delvaux E et al. Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer’s disease patients. Neurobiol Aging. 2013; 34(9): 2091–2099.

Johnson KC, Houseman EA, King JE et al. 5-Hydroxymethylcytosine localizes to enhancer elements and is associated with survival in glioblastoma patients. Nat Commun. 2016 Nov 25;7:13177.

Iatrou A, Kenis G, Rutten BP et al. Epigenetic dysregulation of brainstem nuclei in the pathogenesis of Alzheimer's disease: looking in the correct place at the right time? Cell Mol Life Sci. 2017;74(3):509-523.
Li X, Liu Y, Salz T et al. Whole-genome analysis of the methylome and hydroxymethylome in normal and malignant lung and liver. Genome Res. 2016;26(12):1730-1741.

Raiber E-A, Beraldi D, Martínez Cuesta S et al. Base resolution maps reveal the importance of 5-hydroxymethylcytosine in a human glioblastoma. Genomic Medicine 2017;2:6.

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