Disrupted gene expression underlies many autoimmune diseases and cancers. Dr Paweł Trzaskoma, head of a new laboratory at the Nencki Institute, wants to trace these abnormalities back to their source by examining what happens during transcription – the process of reading the information encoded in DNA. A better understanding of these fundamental cellular mechanisms could help identify new therapeutic targets and support the development of more precise treatment strategies in the future.

The human body contains thousands of genes, and their activity is not constant. Genes can become active at intervals – sometimes separated by several days – producing RNA molecules. This process, known as transcription, is controlled in part by proteins called transcription factors. If a mutation makes one of these factors overactive, RNA levels may rise, reflecting increased expression of the genes it regulates. Measuring this increase is relatively straightforward. The harder question is why it happens.

– We may see that a cell carrying a particular mutation produces more RNA, but that result alone does not tell us why. We want to find out whether the gene becomes active more frequently, whether each period of activity produces more RNA, or whether both mechanisms are involved. This will allow us to identify which part of gene regulation is disrupted by a particular mutation and where therapeutic interventions targeting transcription might be possible – explains Dr Paweł Trzaskoma.

This matters because the next step in the process, known as translation, uses the information contained in RNA to produce a specific protein. Excessive levels of certain proteins can contribute, among other things, to the development of autoimmune disease.

Sequencing and advanced microscopy

Dr Paweł Trzaskoma was selected in an international competition for a group leader position at the Nencki Institute, conducted by the Institute’s International Advisory Board. After completing his PhD at the Nencki Institute, he moved to the United States, where he spent seven years at the National Institutes of Health, one of the world’s leading biomedical research institutions. There, he developed expertise in RNA sequencing methods. Among the factors that encouraged him to return to Poland were the advanced microscopy capabilities available at the Nencki Institute.

– Combining his unique expertise with the exceptional infrastructure and experience of our Institute opens up new opportunities for Dr Paweł Trzaskoma and enables him to pursue ambitious, cutting-edge research at the highest international level, in an environment that offers outstanding conditions for this kind of work – says Prof. Agnieszka Dobrzyń, Director of the Nencki Institute.

From clinical observation to the laboratory

Dr Trzaskoma hopes that, through close collaboration between molecular biologists and physicians, his new laboratory will become a place where the molecular basis of still poorly understood diseases can be investigated. One condition he plans to study is disabling pansclerotic morphea – an ultra-rare systemic autoinflammatory disease characterised, among other symptoms, by impaired wound healing and muscle atrophy. The disease can be caused by mutations in the STAT4 gene, which encodes a transcription factor.

– Working at NIH, in the world’s largest hospital devoted entirely to clinical research, showed me first-hand how valuable direct collaboration between physicians and scientists can be. If a patient is found to carry a new, previously unknown mutation, we can create a cellular model of that mutation and then examine exactly how it changes gene activity. This, in turn, can be crucial for identifying effective treatment strategies. I would like physicians and molecular biologists to work together more often and look at the same problems from different perspectives – says Dr Trzaskoma.