Transcriptional regulation of essential tissues by pioneer factor FoxA in schistosome parasites

Project Summary/Abstract Schistosomes are parasitic flatworms that cause schistosomiasis, a debilitating disease afflicting over 250 million people. Current treatment is limited to a single chemotherapeutic, praziquantel, which is only active against adult parasites, does not prevent reinfection, and has had reports of resistance in schistosomes. This highlights a dire need for new treatments, and shows that a deeper understanding of the mechanisms schistosomes use to operate in our bodies is needed to identify new targets for treatment of this disease. We recently discovered Schistosoma FoxA, a transcription factor that is required for the development and maintenance of the esophageal gland (EG), which is a specialized digestive organ. RNAi depletion of foxA results in complete loss of the EG, which renders parasites unable to survive inside of the host. However, the mechanism by which FoxA regulates transcription, what cofactors are involved in this process, and whether FoxA plays a role in the differentiation of other tissues remains unknown. In other organisms, FoxA is a pioneer transcription factor that binds to and opens chromatin, working with specific co-factors to govern cell fate by regulating the accessibility of certain lineage-associated genes. My preliminary single-cell RNA-sequencing data has revealed that foxA is expressed in discrete cell types, including a specific population of stem/progenitor cells, the intestine, a sub- population of neurons, and at lower levels in the EG. Interestingly, the top two genes that correlate with foxA expression are gata4 and prdm1, which encode transcription factors that are known in other organisms to work with FoxA to govern cell differentiation. Based on these observations, I hypothesize that schistosome FoxA works cooperatively with Gata4 and/or Prdm1 on enhancers of different lineage-specific genes to alter chromatin accessibility, thereby regulating the differentiation of foxA+ stem cells into physiologically important parasite tissues. To test this, I will identify the genes and chromatin regions regulated by FoxA using single-nuclei multi- omics of control and foxA RNAi parasites (Aim 1) and define the roles of Gata4 and Prdm1 in parasite tissue maintenance and survival in the host using RNAi coupled with high-resolution imaging and robust in vivo assays (Aim 2). This work will elucidate the molecular mechanisms by which FoxA regulates the development of essential parasite tissues, aiding in the identification of parasite factors with potential to be targeted for treatment of this disease. Together with Dr. Jayhun Lee (sponsor) and Dr. Ambro van Hoof (co-sponsor), I have created a plan to achieve the work proposed here, as well as develop my skills and transition to a post-doctoral fellowship. As such, the Lee lab and UTHealth Houston provide the ideal environment to hone both my research and professional skills, helping me to achieve my long-term goal of becoming a successful independent researcher.