Uncovering the role of enhancers in disease progression
Cells that function in the immune system will express a different subset of genes than, say, a liver cell. Enhancers, regulatory DNA sequences that are bound by specific proteins, play an important role in determining where and when genes are expressed in different cells in the body. “Understanding the intricate dance of these regulatory elements could shed light on the complex mechanisms governing our biology,” explains ENHPATHY project coordinator Salvatore Spicuglia from Inserm in France. “It is also increasingly clear that disruptions to the finely tuned control of gene expression can lead to disease susceptibility or progression.”
Enhancer-based diagnostic and therapeutic tools
The EU-funded ENHPATHY project sought to investigate the role of enhancers in disease progression. Supported by the Marie Skłodowska-Curie Actions programme, a multidisciplinary training initiative was established to support researchers with skills in genomics, bioinformatics and clinical research. “The primary goal was to build a deeper understanding of the mechanisms underlying enhancer dysfunction,” says Spicuglia. This research was organised in three sections. The first was about understanding the features that control enhancer activity, and how a specific mutation can alter the function. The second focused on unravelling how enhancers work within complex regulatory cascades. Third, the project team focused on identifying disease-causing enhancer alterations and laying the foundation for the development of new enhancer-based diagnostic and therapeutic tools.
Genetic testing of enhancer variants
Spicuglia co-supervised research into acute myeloid leukaemia (AML), a form of cancer that affects white blood cells. The reasons behind resistance to certain drugs in AML patients were investigated. “In collaboration with Advanced BioDesign, we identified enhancers that get activated in cells when exposed to a drug used in chemotherapy,” notes Spicuglia. “This causes resistance to treatment. The next step is to prevent cells from developing resistance by directly targeting those enhancers.” Led by Wouter de Laat at the Hubrecht Institute in the Netherlands, researchers also explored therapeutic possibilities for combating genetic diseases. Researchers worked on new approaches to treating thalassaemia, an inherited condition that affects the body’s ability to produce haemoglobin, a protein that transports oxygen around the body. “Repositioning beta-globin enhancers was shown to rescue or recover haemoglobin expression,” says Spicuglia. Another investigation, led by Jorge Ferrer, programme coordinator at the Centre for Genomic Regulation, in Barcelona, investigated the molecular mechanisms behind different forms of diabetes. “By combining information from enhancer variants and coding variants, we can develop diagnostics, particularly for young people with the disease,” explains Spicuglia. “Genetic testing of enhancer variants will likely play a key role in diagnosing diabetes in future.”
New avenues for diagnosis, treatment and prevention
Spicuglia believes that a deeper understanding of regulatory mechanisms can lead to more effective therapeutic strategies. “While a lot of attention in the project was focused on investigating the underlying mechanisms behind enhancer dysfunction, we also wanted to translate our findings into new therapies and improved diagnostic techniques,” he remarks. In this regard, the ENHPATHY consortium recently identified critical areas for further investigation. This work was published in a peer-reviewed journal. “By shining a spotlight on this previously overlooked landscape, we are uncovering a treasure trove of information,” adds Spicuglia. “This promises to illuminate the intricate molecular mechanisms behind a myriad of diseases, offering new avenues for diagnosis, treatment and prevention.”
Keywords
ENHPATHY, cancer, diagnosis, immune, disease, genes, genetic, AML
