About the Project
Essentially all eukaryotic nucleated cells exploit various features of nuclear architecture and chromatin modification to control expression of genes. One highly significant mechanism is heterochromatinisation, the process by which specific regions of chromatin become compacted and less amenable to transcription. This is a highly efficient process, and can result in repression of affected loci by 105 or 106 fold, compared to promotor modulation, which is typically 100-fold. For this reason, imprinting and developmental regulation of important genes is frequently a heterchromatinisation-driven process.
Trypanosomes are important pathogens that afflict much of the world, and which also use heterchromatinisation-based mechanisms. However, the proteins mediating this process are poorly characterised at present, as is the structure and configuration of the heterochromatin. This project will build upon recent work that has identified and characterised several proteins that constitute the nuclear lamina, and will characterise DNA-protein and protein-protein interactions, together with Hi-C mapping of heterochromatin. It is anticipated that the outcomes of this project will provide new insights into the novel mechanisms that trypanosomes use to drive heterochromatinisation, as well as potentially identify new therapeutic targets.
References
Codependence between Trypanosoma nuclear lamina components in nuclear stability and control of gene expression. Maishman, L., Obado, S., Alsford, S., Bart, J.M., Navarro, M., Horn, D., Ratushny, Aitchison, J.D., Chait, B.T., Rout, M.P., and Field, M.C., (2016) Nucleic Acids Research 44 10554-10570
Ancient eukaryotic origin and evolutionary plasticity of the nuclear lamina. Koreny, L., and Field, M.C., (2016) Genome Biology and Evolution 8 2663 - 2671
Interactome mapping reveals the evolutionary history of the nuclear pore complex. Obado, S., Brillantes, B., Uryu, K., Zhang, W-Z., Ketaren, N.E., Chait, B.T. Field, M.C., and Rout, M.P. (2016) PLoS Biology 14 e1002365