The epigenetic role of MORC in apicomplexan life cycle stage development and virulence – ApiMORCing

The related Apicomplexa parasites Toxoplasma gondii and Plasmodium falciparum are the causative agents of the human diseases toxoplasmosis and malaria, respectively. These diseases still have a major global health impact due to the parasite’s ability to survive in and cycle through different host environments. For both parasites, each developmental transition in the life cycle is driven by the timely expression of a specific repertoire of genes. Curiously, apicomplexans lack most of the canonical specific transcription factors found in other eukaryotes, but they do encode a unique family of transcription factors containing plant-like Apetala2 DNA-binding domains. Several of these Apicomplexan AP2 (ApiAP2) factors were shown to be important drivers of life cycle transitions. For example, AP2-G is the master inducer of sexual differentiation in P. falciparum and is kept tightly silenced during asexual replication. However, the molecular mechanisms by which AP2 factors regulate stage-specific genes and how they themselves are regulated are poorly understood.

The backdrop to this project is an emerging field of parasite epigenetics that has followed in the footsteps of epigenetics in model eukaryotes. Importantly, parasites offer a unique system in which to study epigenetic transcriptional control, as they must survive in and transition quickly between extremely different host environments. Each step in the life cycle requires a specific cohort of genes, and the goal is to understand the epigenetic mechanisms controlling these precisely-timed transcriptional programs. Many similarities, but also many key differences, in epigenetic mechanisms have been discovered between parasites and model organisms.

This proposal is based on our discovery in apicomplexan parasites of the epigenetic regulator MORC, a family of proteins that act in chromatin compaction in plants and animals. MORC plays a crucial role in sexual commitment in T. gondii. Indeed, TgMORC associates with multiple ApiAP2 transcription factors and represses genes involved in sexual differentiation. In addition, TgMORC binds to telomeric sequences and represses transcription in these regions. These important discoveries represent a paradigm shift in the study of heterochromatin-mediated gene silencing in Apicomplexa. In P. falciparum, we found MORC in a complex that binds to the promoters of var genes, a family of 60 genes that encode the most important variant surface antigen involved in parasite virulence. Thus, our preliminary data have identified ApiMORC as an important new player in controlling transcriptional programs that facilitate Apicomplexan parasite virulence and transmission.

Using a multidisciplinary approach based on Next Generation Sequencing techniques and proteomics in two different Apicomplexan parasites, the project ApiMORCing will dissect the molecular mechanisms by which MORC 1) achieves targeting to specific loci, including telomeric regions and genes underlying virulence and sexual differentiation and 2) represses gene expression and/or facilitates heterochromatin formation. We will also explore the contribution of the network of AP2 TFs that acts downstream of MORC to guide developmental trajectories.

Understanding the fundamental principles of transcriptional control in these parasites will shed light on how they make dramatic transitions from asexual replication to sexual differentiation, as well as how they survive in their respective hosts. In addition, MORC may be involved in the maintenance of genomic integrity via protection of telomeric sequences. Elucidating the mechanism of ApiMORC targeting and function in these diverse processes will reveal pathways that could be targeted with therapeutics. Therefore, the proposed research has direct implications for the Health and Well-being objective of sustainable development, which seeks to end epidemics of communicable diseases, including malaria.