Exploring the Epigenetic Landscape with the Six-Base Genome

Unlocking the Secrets of the Six-Base Genome

Epigenetics was somewhat vague when I was an undergraduate ( a long time ago). So I was curious to get an update on how we can investigate it more closely and what we are learning. I talked to Tom Charlesworth, Director of Market Strategy and Corporate Development at biomodal, a sequencing technology company focused on epigenetics. Tom explained how modifications beyond the traditional four DNA bases impact gene expression, development, and disease.

What is the Six-Base Genome?

Tom introduced biomodal as a sequencing technology company spun out of the University of Cambridge, focused on the interface between genetics and epigenetics. Their technology goes beyond the traditional four-base genome (A, T, G, and C) by adding two epigenetically modified bases: methylcytosine (5-MC) and hydroxymethylcytosine (5-HMC). This “six-base” approach captures critical modifications that play distinct roles in gene regulation.

5-MC is associated with repressing gene expression, often keeping certain genes “turned off,” while 5-HMC is linked to opening chromatin and activating gene expression. Understanding these modifications provides a more dynamic picture of how our genes are regulated—not just by the sequence of DNA but also by chemical marks that change over time.

Bridging the Gap Between Genetics and Function

The traditional four-base genome gives us an invaluable map of our genetic code, but it falls short of explaining how the same genetic sequence could lead to such diverse outcomes—from development to disease. Epigenetic modifications, like 5-MC and 5-HMC, offer another layer of regulation that’s essential for gene expression.

Tom highlighted research that illustrates the value of this additional information. He mentioned the work of developmental biologist Emily Hodges, who uses the six-base data to study chromatin accessibility during neuronal stem cell differentiation. Emily found that early changes in 5-HMC could predict chromatin opening, an insight that would be invisible if one only looked at 5-MC. This kind of nuanced view helps us understand the precise moments when genes are primed for activation, offering a clearer picture of developmental biology.

Applications From Oncology to Neurology

Tom described three main areas where their customers are leveraging the six-base genome: fundamental research, oncology, and neurology.

In oncology, there’s a growing recognition that multi-omic data—integrating genetic and epigenetic information—can improve cancer detection and treatment response. Tom shared examples of ongoing projects in Canada and Australia, where researchers are using six-base sequencing to better understand the complex dynamics of tumor evolution. By distinguishing between 5-MC and 5-HMC in circulating tumor DNA, they hope to pinpoint which DNA fragments originate from cancer cells, providing a more accurate snapshot of the disease’s state and progression.

The six-base genome also shows promise in neurology. Tom explained that the brain is unique because it has an unusually high level of 5-HMC compared to other tissues, yet we still don’t fully understand why. Early research is exploring this epigenetic landscape to uncover new biomarkers for diseases like Parkinson’s, Alzheimer’s, and various brain tumors. The ability to profile these epigenetic marks could lead to breakthroughs in diagnosing and potentially treating neurological disorders.

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Epigenetics as a “Life Record”: The Developmental and Environmental Context

Here’s another way think about the six-base genome—as a record of a cell’s developmental journey and its responses to the environment. During early development, epigen