What makes a parasite tick? Dissecting gene regulatory mechanisms in Plasmodium falciparum
05 / 2012 - onbekend
A well-timed gene expression program provides the foundation for the 48h developmental cycle of malaria parasites within human red blood cells and is thereby indirectly responsible for all disease-related symptoms and mortality. Dissecting regulatory mechanisms underlying this unique expression program therefore is mandatory to understand parasite development and could provide crucial information for drug-based intervention. The lack of a genome-wide, quantitative framework around the regulation of gene expression represents a major hurdle for the translation of sporadic experimental observations into regulatory models. Consequently, it is largely unresolved which transcriptional factors govern parasite development and how chromatin organization contributes to its regulation. Furthermore it has remained a mystery how gene regulatory mechanisms have adapted to function on the extremely AT-rich Plasmodium genome (average 83% adenine and thymine). I have recently established a unique method for next generation sequencing that for the first time enabled high-resolution analysis of the transcription factor binding sites and chromatin organization in Plasmodium, which has placed my mini group at the forefront of malaria epigenome research. The aim of this proposal is to provide the missing quantitative framework by dissecting transcriptional and epigenetic gene regulatory mechanisms in the context of the entire Plasmodium genome and define their importance in driving parasite development. My main objectives are: i) to unveil the function of the transcription factor regulatory network during parasite development; ii) to gain mechanistic and functional insight to the deposition and positioning of nucleosomes (the ?building blocks? of chromatin) at the extremely AT-rich gene regulatory regions. Parallel examination and correlation of two distinct, but intertwined processes (transcription factor binding and chromatin organisation) will provide comprehensive insight into gene regulatory mechanisms that govern parasite development. Furthermore it will reveal insight that can ultimately lead to novel strategies to combat this deadly parasite.