Epigenetics reveals new therapeutic opportunities once thought inaccessible

Rocket science often gets used as an example of the most complex endeavor there is and evokes images of mission control with a board of switches, dials, circuits and screens that determine how the myriad components of a successful rocket launch behave. Arguably more complex than rocket science, in biology, cells have their own version of mission control. DNA provides the blueprint, but epigenetics is the system that controls how and when genes are used. It determines which genes are active, when and how strongly. 

When epigenetic circuitry is disrupted, the consequences can be profound, contributing to cancer, neurologic disorders and blood diseases. For decades, many of the proteins involved in epigenetic pathways were considered beyond the reach of medicine because these proteins often lacked the features traditional drugs rely on to bind targets, leading researchers to label them “undruggable.” Today, that perception is changing due to new technical abilities — opening a door for novel therapies. St. Jude scientists are leveraging these abilities to create options for treating pediatric diseases in need of effective, more tailored treatments. 

Reaching previously inaccessible switches 

Charles W.M. Roberts, MD, PhD, St. Jude executive vice president and Comprehensive Cancer Center director, studies cancers driven by mutations in chromatin remodeling complexes, which help organize DNA so genes can be accessed. These mutations disrupt the regulatory systems that control gene activity, contributing to aggressive cancers such as rhabdoid tumors. 

Even when the mutated proteins cannot be directly targeted, the disruption can expose new vulnerabilities. “Chromatin proteins and transcription factors function in interconnected regulatory networks,” Roberts said. “When one component is mutated, we’ve found that other proteins become dependencies for the cancer cell.” 

New therapeutic strategies are emerging to exploit these weaknesses. “Many transcription factors and chromatin regulators have been difficult targets because they lack obvious binding pockets,” said Roberts. “However, new classes of drugs, often called degraders, along with advances in structural biology, are revealing ways to target proteins that previously seemed inaccessible.” 

Together, these approaches are giving researchers new ways to manipulate parts of the cellular control board that once seemed untouchable. 

One wiring system, many diseases 

Better understanding epigenetics has also helped explain why the same genetic mutation can lead to very different outcomes depending on context. Every cell in the body contains essentially the same DNA blueprint, yet only certain cell types develop cancer. 

The difference lies in how the cellular circuitry is configured. 

Heather Mefford, MD, PhD, Department of Genomic & Translational Neuroscience, studies children with epilepsy and neurodevelopmental conditions caused by disruptions in genes that help control how DNA is organized and used, such as CHD2. 

“These genes are expressed everywhere in the body,” Mefford said, “but when they are disrupted, the effects are often overwhelmingly in the brain.” 

Her research focuses on understanding how disruptions in gene regulation affect brain development. By studying these downstream effects, her team can uncover how they lead to seizures, developmental delays and other neurologic symptoms. 

“Epigenetics lets us ask what happens downstream once that machinery is disrupted,” Mefford said. “We are not just identifying a gene. We are learning what that disruption does.” 

Mapping regulatory vulnerabilities in blood 

This same control system is just as critical in shaping how blood cells develop and function. Yong Cheng, PhD, Departments of Hematology and Computational Biology, studies how regions of DNA that act like switches and boundaries control gene activity as stem cells develop into different types of blood cells. 

“In blood, epigenetic regulation governs how the entire hematopoietic [blood cell formation] system develops and functions,” Cheng said. “Stem cells transition through tightly controlled stages to generate distinct lineages.”

Because these programs are so precisely regulated, even subtle disruptions can lead to disease. One example is the transition from fetal to adult hemoglobin, a developmental switch controlled by epigenetic mechanisms such as DNA methylation and regulatory DNA elements that activate or deactivate genes.

“The fetal to adult hemoglobin switch is fundamentally an epigenetic transition,” Cheng said. “Understanding that regulatory program has opened therapeutic opportunities for disorders such as sickle cell disease.” This includes genome editing that reactivates fetal hemoglobin, which has shown promise to one day help those with sickle cell disease and beta-thalassemia.

Cheng’s laboratory is working to decode what he describes as the “epigenetic grammar,” or the rules that determine how these DNA control elements work together. 

“We want to understand not only where these control elements are located, but how they function together to control gene expression.”

From discovery to patient impact

Modern technologies have enabled scientists to map these regulatory systems in unprecedented detail. Researchers can use advanced tools to measure many layers of biology at once, including DNA changes and gene activity across cell types.

For Mefford’s team, genome-wide methylation profiling has become an important diagnostic tool. “Methylation arrays let us do one test and ask many different questions,” she said. 

By identifying disease-specific molecular patterns, clinicians can determine whether certain genetic changes are likely to cause disease. For families searching for answers, that clarity can be life-changing, turning uncertainty into a path forward.

Meanwhile, Roberts and his colleagues aim to translate these insights into new cancer therapies. In addition to targeting gene-regulating proteins directly, they are identifying downstream weaknesses that cancer cells rely on more heavily than normal cells.

Epigenetic insights are beginning to reshape how therapies themselves are designed. Researchers are using these approaches to reprogram a type of immunotherapy approach called chimeric antigen receptor (CAR) T cells, extending how long they persist in the body and how effectively they attack cancer. 

By tuning the same regulatory systems that control cell behavior, these strategies aim to create more durable responses and push cellular therapies beyond their current limits. 

Toward pathway-based medicine

Researchers believe these insights may shift medicine toward targeting shared biological programs rather than individual mutations. “In many diseases, the underlying issue is that a regulatory program has gone wrong,” Cheng said. “If we understand that regulatory logic, we can identify precise control points for intervention.”

At St. Jude, collaboration across disciplines is accelerating these discoveries. Scientists studying cancer, neurologic disease and blood disorders are uncovering common principles governing how cells interpret and implement genetic instructions.

As researchers continue mapping these biological control systems, targets once considered unreachable are becoming increasingly accessible. 

The switches are no longer out of reach.