Exploring the Epigenetic Landscape with the Six-Base Genome

Unlocking the Secrets of the Six-Base GenomeEpigenetics 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 FunctionThe 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 NeurologyTom 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.Are you subscribed yet? If not, let’s fix that.Epigenetics as a “Life Record”: The Developmental and Environmental ContextHere’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, epigenetic marks guide cells down specific paths, setting up the blueprint for tissues and organs. But later in life, these marks are influenced by external factors like diet, aging, and environmental exposures. This can lead to changes in gene expression that contribute to disease, aging, or even resilience against external stressors.We also touched on how this concept applies to reprogramming cells, such as in induced pluripotent stem cells (IPSCs). When cells are reprogrammed, they don’t just revert to a blank slate; their epigenetic history still influences how they behave. Tom described work showing that successful reprogramming often involves restoring specific epigenetic marks, essentially rewinding the “epigenetic clock” to a more youthful state.Rethinking DNA as the Sole BlueprintTraditionally, DNA has been viewed as the ultimate blueprint for life. But the static genome represents only a portion of the story—it’s the interaction with the adaptable epigenome that truly dictates how our genetic potential is realized. The six-base genome isn’t just a scientific curiosity; it’s another tool for decoding the complexities of life.Tom describes DNA as the “possibility space” of an organism, but it’s the epigenetic modifications that trim and shape this space into the reality we observe. This nuanced view challenges us to look beyond the sequence and consider the rich layers of regulation that determine who we are and how we function.I am most excited to learn how environmental conditions like diet and maybe even experience influence the epigenome. As a bacterial geneticist, my basic model is substance A interacts with some regulatory protein to turn a gene on or off. I want to know how the epigenome records my environment. Do the conversations I have had leave detectable marks on the chromosomes in my brain? What would be the mechanism for that? Regardless of the outcome, it’s fun to see the ever increasing depth of our understanding of biology.Your deepest insights are your best branding. I’d love to help you share them. Chat with me about custom content for your life science brand. Or visit my website.If you appreciate this content, you likely know someone else who will appreciate it too. Please share it with them. This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit cclifescience.substack.com