African trypanosomes are unicellular parasites that cycle between tsetse flies and mammals, including humans and their livestock. They captured my imagination and became the focus of my research for two reasons: they are agents of human sleeping sickness and the animal disease Nagana in the country I grew up in—Zimbabwe—and they have an unorthodox cell biology, which constantly takes us by surprise. I first started working on these parasites as a postdoc in Merv Turner's "Antigen Group" in Cambridge, which, like most trypanosome groups at the time, worked on the variant surface glycoprotein (VSG) coat of bloodstream forms. While looking for genes that were expressed exclusively at this stage of the life cycle, I discovered the genes for procyclins—the major coat proteins of procyclic (tsetse midgut) forms—in what was supposed to be a negative control. Since then my research has concentrated on stage-specific gene expression and the signals that guide trypanosomes to differentiate and migrate at various points in their life cycle. Recently, our search for the stage-specific coat of epimastigote (salivary gland) trypanosomes—this time deliberately—culminated in the identification of the BARP family of proteins. My laboratory is also interested in how trypanosomes regulate gene expression in response to changes in their milieu, as the insect forms in particular are confronted with fluctuations in temperature, variation in nutrients, and the presence of other microbes.
Many features of gene expression in trypanosomes are unusual, and some are unique. Trypanosomes were the first eukaryotes shown to have genes organized in polycistronic transcription units (which were previously only known in bacteria); they also provided the first example of trans-splicing between the leader and the body of messenger RNAs. Most protein-coding genes in T. brucei are transcribed by RNA polymerase II, as they are in other eukaryotes, but transcription of procyclin and VSG genes is performed by RNA polymerase I (which, in other organisms, is restricted to transcribing ribosomal RNAs). Like ribosomal RNAs, procyclins are transcribed in the nucleolus, while the VSG is transcribed in a specialised nuclear compartment, the expression site body. The procyclin and VSG promoters were defined more than 20 years ago. Until recently, however, it was thought that the Pol II transcription units did not have discrete initiation sites, and it is still widely believed that they are not subject to transcriptional control. The steady-state levels of transcripts from genes within a polycistronic transcription unit can vary considerably, but this has usually been attributed to differences in mRNA stability. With few exceptions, transcripts from a single transcription unit are not coordinately regulated, nor are they organized in operons according to function. This has given rise to the concept of post-transcriptional regulons—cohorts of mRNAs, transcribed from dispersed regions of the genome, which are controlled by common sets of RNA-binding proteins.
While the importance of post-transcriptional control for adjusting gene expression is undisputed—and a long-standing topic of our research—we have evidence that chromatin marks within transcription units may provide a previously unsuspected level of control. Another area that we are exploring is how trypanosomes within a community interact with each other and how surface proteins determine their behavior. Finally, a large-scale screen for a new type of drug against sleeping sickness, in which we use transgenic trypanosomes to identify compounds that trigger premature procyclin expression and loss of the VSG coat, is an important spin-off of our basic research.
In addition to support from HHMI, work in our laboratory is financed by the Swiss National Science Foundation, the Canton of Berne, and the Velux Foundation. A collaboration with the Swiss Tropical and Public Health Institute is supported by the Bill and Melinda Gates Foundation.
As of September 26, 2012