The purpose of this project is to understand how parasites adapt to different environments as they move between organisms. The African trypanosome is an example of one such parasite that moves between the blood of infected animals and the tsetse fly. When a tsetse fly bites a human or a hooved animal, parasites are transferred to the bloodstream and cause a fatal disease called African trypanosomiasis (sleeping sickness). Understanding how the parasites adapt to each environment is important for understanding the dynamics of infection in regions where the disease is endemic. In addition, because African trypanosomes diverged very early from other well studied model organisms, understanding the gene regulation that occurs as parasites adapt to different environments will shed light on how gene regulatory systems evolved. The study of parasite adaptation in a research lab setting will provide opportunities for first- generation high school students and first year college students underrepresented in STEM fields to forge close connections with a research mentor, which is important for retention in the field. Students will also be given the opportunity to pursue open ended projects on parasite adaptation in a classroom laboratory setting, ideally increasing their confidence and interest in joining a research lab.

The trypanosome (T. brucei) genome is organized into large polycistronic transcription units of functionally unrelated genes. No DNA sequence-specific transcription factors have been identified, nor are there obvious promoter sequences. Histone modifications also differ substantially from other eukaryotes. The lack of sequence specific transcription factors in T. brucei have led some to hypothesize that they harbor a ‘primitive’ version of the histone code. Despite these differences, substantial transcriptome reprogramming is required to facilitate the huge changes in morphology and metabolism that occur as parasites cycle between the tsetse fly vector and the bloodstream of infected mammals. The molecular mechanisms that drive these large- scale changes in the transcriptome are poorly understood. The premise of this research project is that chromatin interacting bromodomain proteins act as key modulators of transcriptome reprogramming in parasites adapting to a new host. This premise will be investigated by 1) determining whether bromodomain proteins are required for maintenance of the midgut transcriptome in insect-stage parasites using RNA-seq, 2) characterizing the changes in bromodomain protein occupancy that occur during parasite adaptation from the bloodstream to the insect stage using CUT&RUN, and (3) determining the knockdown phenotype of candidate genes proximal to areas of dynamic bromodomain protein occupancy as parasites transition from the bloodstream to the insect stage. This knowledge is expected to highlight differences in gene regulation in a eukaryote that diverged early from better studied model systems.

This award was cofunded by the Symbiosis, Infection and Immunity Program in the Division of Integrative Organismal Systems.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

National Science Foundation (NSF)
Division of Molecular and Cellular Biosciences (MCB)
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Candi Phoebe Lostroh
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Harvey Mudd College
United States
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