An Exploration of Transcriptional Regulation in the Human Malaria Parasite, Plasmodium falciparum

Malaria is one of the most lethal infectious diseases in many developing countries. Approximately half of the world’s population is at risk of malaria transmission, and this number can be expected to grow as drug resistant strains continue to develop. Among the human infectious Plasmodium species, Plasmodium falciparum causes the most severe and lethal form of malaria. This parasite has an extreme AT-rich genome and a complex life cycle that is likely to be regulated by coordinate changes in gene expression. However, the mechanisms behind this fine-tuned gene expression and regulation system remain elusive. For instance, only a limited number of transcription factors have been identified. Recent studies suggest that epigenetic and post-transcriptional regulation may be used as alternative regulation strategies to compensate for the lack of transcription factors in this parasite. Therefore, in this dissertation work, we further explored the transcriptome, epigenome, and the proteome to better understand the transcriptional mechanisms in P. falciparum. In chapter 1, we demonstrated that genes are usually defined by unique nucleosomal features and that nucleosome landscape alone could be used to identify novel genes in organisms with a nucleotide bias. Next, we investigated nascent RNA expression profiles and observed that the majority of genes are transcribed at the trophozoite stage in response to the open chromatin structure of that stage. These results helped us link chromatin reorganization events to transcriptional activity and highlighted the importance of epigenetic and post-transcriptional regulation in this parasite. Therefore, in the latter two chapters, we further examined the proteasome and transcriptome isolated from both nuclear and cytoplasmic fractions to identify potential chromatin regulators. As a result, we identified a large number of chromatin-associated proteins and lncRNAs that are likely to have important roles in chromatin regulation and post-transcriptional and translational regulations. Collectively, data and results from these studies will become stepping-stones for future malaria studies and further assist the identification of promising anti-malarial drug targets