Pathological Condensates and Transcription Dysregulation in Rhabdomyosarcoma at Single-Molecule Resolution
Intrinsically disordered protein regions (IDRs), part of the “dark matter of biology”, are extremely abundant in the protein kingdom. How IDRs perform functions in the cell is not well understood due to a lack of tools to study them. Since numerous known disease mutations occur in IDRs, our lack of understanding of IDRs represents a major hurdle for developing therapeutics. My lab strives to understand how IDRs play a role in regulating gene transcription in the context of physiology and disease. Transcription, the process by which a gene’s DNA is converted to RNA, is fundamental to all cellular functions. We are particularly interested in transcription factors (TFs), proteins that activate transcription through their intrinsically disordered “low-complexity domains (LCDs)”. It has been a long-standing mystery how LCDs enable transcription. We recently developed powerful new optical imaging tools to visualize and track TF LCD molecules one at a time in live human cells. Using these tools, we discovered a new type of protein-protein interactions between LCDs, which drive the formation of TF assemblies at specific genes and enable gene transcription. Importantly, we found several cancer-causing proteins form aberrant assemblies via the same type of LCD-LCD interactions. This behavior is important for the development of different cancers, e.g., Ewing sarcoma, Wilms tumor, and acute myeloid leukemia. Our findings have shed new light on the causes and therapeutics of the cancers.
Project Goal:
This ALSF Innovation Grant project focuses on rhabdomyosarcoma, the most common soft tissue cancer of childhood and adolescence, which remains poorly managed with standard treatments. Due to a far-from-sufficient understanding of the cause of rhabdomyosarcoma, little progress has been made in developing targeted therapies for this devastating cancer. Among the two major subtypes of rhabdomyosarcoma, the more aggressive is alveolar rhabdomyosarcoma (aRMS). The aberrant transcription factor PAX3-FOXO1 is a hallmark protein that is found in 60% of all aRMS cases and considered an attractive target for drug development. We hypothesize that PAX3-FOXO1 similarly forms aberrant assemblies at specific genes via its LCD-LCD interactions, and this behavior results in transcription dysregulation that ultimately causes aRMS. We will employ a suite of powerful, cutting-edge live-cell imaging and chemical biology techniques that we recently developed and a comprehensive set of functional assays to pursue the research aims. With the support of Alex’s Lemonade Stand Foundation, the proposed study promises to shed new light onto aRMS causes and suggest a novel therapeutic strategy for aRMS. Since many childhood cancers, including pediatric leukemias and sarcomas, are associated with aberrant, LCD-containing proteins like PAX3-FOXO1, our findings and novel scientific tools developed in this project will pave the way for understanding and developing therapies for many other types of cancer.
