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Identification of Specific Proteins Can Aid in Development of Novel Therapeutic Targets for Heart Diseases

Researchers from Duke-NUS have developed the first genome-wide dataset on protein translation during fibroblast activation during cardiac fibrosis.

Using cutting-edge technologies, researchers at Duke-NUS Medical School, Singapore, have revealed a network of RNA-binding proteins (RBP) that play a key role in the formation of disease-causing fibrous tissue in the heart. Their findings, published in the journal Circulation, could assist in the search for new therapeutic targets.

Cardiac fibrosis, a condition characterised by scarring in the heart, is caused by the activation of fibre-producing cells called fibroblasts. The transformation of fibroblasts to myofibroblasts, will lead to the thickening and stiffening of the heart wall, making it less contractile and thus less efficient in pumping blood throughout the body.

Computational geneticist Dr Owen Rackham, corresponding author of the study and Assistant Professor in the Cardiovascular and Metabolic Disorders (CVMD) Programme at Duke-NUS explains, “Despite the serious risk and high prevalence of cardiac fibrosis, existing therapies are ineffective and there is an unmet need for new therapeutic approaches to prevent, limit, or reverse the condition.”

The team of researchers from Duke-NUS and colleagues in Germany and the UK investigated the processes that regulate the transcription of DNA code into RNA, and the translation of that code from RNA for protein synthesis during the transformation of fibroblasts into myofibroblasts.

Specifically, the researchers found RBPs play critical roles in the fibroblast-to-myofibroblast transformation. RBPs target RNA, affecting the translation of its code during protein synthesis. Inhibiting two of these RBPs, called PUM2 and QKI, limited the transformation of fibroblasts into myofibroblasts.

“We found a staggering one-third of all genes undergo translational regulation during this pathogenic transition,” highlighted Ms Sonia Chothani, first author of the study and a PhD student at Duke-NUS. “All these gene expression changes are missed or misinterpreted in traditional RNA-based studies.”

From this study, the researchers recommend future research to carefully reveal the interdependencies and cross-interactions in the various stages of gene expression to have a better understanding of the regulatory process leading to disease manifestation. [APBN]