The environmental challenges the human malaria parasite, Plasmodium falciparum, faces during its progression into its various lifecycle stages warrant the use of effective and highly regulated access to chromatin for transcriptional regulation. Microrchidia (MORC) proteins have been implicated in DNA compaction and gene silencing across plant and animal kingdoms. Accumulating evidence has shed light on the role MORC protein plays as a transcriptional switch in apicomplexan parasites. In this study, using the CRISPR/Cas9 genome editing tool along with complementary molecular and genomics approaches, we demonstrate that PfMORC not only modulates chromatin structure and heterochromatin formation throughout the parasite erythrocytic cycle, but is also essential to the parasite survival. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) experiments suggests that PfMORC binds to not only sub-telomeric regions and genes involved in antigenic variation but may also play a role in modulating stage transition. Protein knockdown experiments followed by chromatin conformation capture (Hi-C) studies indicate that downregulation of PfMORC impairs key histone marks and induces the collapse of the parasite heterochromatin structure leading to its death. All together these findings confirm that PfMORC plays a crucial role in chromatin structure and gene regulation, validating this factor as a strong candidate for novel antimalarial strategies.
Keywords: P. falciparum; chromatin; chromosomes; epigenetic; gene expression; gene regulation; infectious disease; malaria; microbiology.
Malaria is an infectious disease caused by parasites that spread to humans through mosquitoes. The parasite species Plasmodium falciparum accounts for the most fatal forms of the disease and can undergo substantial genetic changes that allow it evade detection by the human immune system. A better understanding of how P. falciparum controls its gene expression could help find new ways for treating this aggressive form of malaria. One of the key mechanisms by which cells – including parasites – control gene expression is by remodeling the structure of their DNA, which is tightly packed in to a construct known as chromatin. By loosening or condensing regions of chromatin, cells can make certain genes more or less accessible to the machinery responsible for activating them. Recently, a protein called MORC has been found to play a key role in chromatin remodeling and gene expression in different parasites, plants and animals. However, it remains unclear if MORC also influences chromatin structure of P. falciparum and contributes to the parasite’s ability to evade immune detection. To investigate this question, Chahine, Gupta, Lenz, Hollin et al. employed a variety of gene editing tools, including CRISPR/Cas9. This revealed that reducing MORC levels caused the structure of chromatin in P. falciparum to collapse, ultimately resulting in the death of the parasite. The team also found that MORC not only directly interacts with the parasite’s chromatin, but also other factors involved in chromatin remodeling and genes that help the parasite evade the immune system. These findings highlight the essential role of MORC protein in maintaining chromatin structure and the survival of P. falciparum, and offer a new therapeutic target for controlling the spread of this aggressive form of malaria.
© 2023, Chahine, Gupta, Lenz et al.