UC Riverside

Apicomplexan parasites like Plasmodium falciparum and Toxoplasma gondii are responsible for over a half million deaths each year globally. They employ sophisticated epigenetic mechanisms to regulate gene expression and evade host immune responses. This dissertation investigates the epigenetic and chromatin structural features that enable these parasites to coordinate a complex profile of virulence factors and survive within their hosts. Using complementary molecular and genomics approaches including RNA-seq, ChIP-seq, Hi-C, and proteomics, I characterized several key regulatory factors and mechanisms. In P. falciparum, I demonstrated that depletion of repressive H3K9me3 marks and small, localized changes in chromatin structure are required for expression of var2csa, a critical virulence gene involved in establishing the placental binding phenotype and pregnancy-associated malaria. I also showed that deletion of var2csa disrupts coordinated var gene switching by increasing heterochromatin compaction. Additionally, I identified PfMORC as an essential chromatin-associated factor that maintains heterochromatin integrity and transcriptional repression during blood-stage development. In T. gondii, I investigated ROP55, a novel rhoptry protein that promotes parasite survival by preventing lytic cell death. I also revealed how infection reorganizes host cell chromatin architecture through weakening of topologically associating domains and disruption of A/B compartments, providing new insights into host-pathogen interactions. Together, this work advances our understanding of the complex interplay between nuclear organization, chromatin structure, and gene regulation in apicomplexan parasites. The findings highlight the importance of epigenetic mechanisms in parasite virulence and survival, with broad implications for developing novel intervention strategies against these major human pathogens.