Investigation of heterochromatin protein 1 function in the malaria parasitePlasmodium falciparumusing a conditional domain deletion and swapping approach

Abstract

The human malaria parasite Plasmodium falciparum encodes a single ortholog of heterochromatin protein 1 (PfHP1) that plays a crucial role in the epigenetic regulation of various survival-related processes. PfHP1 is essential for parasite proliferation and the heritable silencing of genes linked to antigenic variation, host cell invasion and sexual conversion. Here, we employed CRISPR/Cas9-mediated genome editing combined with the DiCre/LoxP system to investigate how the PfHP1 chromodomain (CD), hinge domain and chromoshadow domain (CSD) contribute to overall PfHP1 function. We show that the C-terminal 76 residues are responsible for targeting PfHP1 to the nucleus. Furthermore, we reveal that each of the three functional domains of PfHP1 are required for heterochromatin formation, gene silencing and mitotic parasite proliferation. Finally, we discovered that the hinge and CSD domains of HP1 are functionally conserved between P. falciparum and P. berghei, a related malaria parasite infecting rodents. In summary, our study provides new insights into PfHP1 function and offers a tool for further studies on epigenetic regulation and life cycle decision in malaria parasites.

Targeting Gametocytes of the Malaria Parasite Plasmodium falciparum in a Functional Genomics Era: Next Steps

“…Recently, parasite factors like genetic determinants driving sexual development have been identified with the discovery of AP2-G as a master regulator of sexual commitment in P. falciparum [ 25 ]. Two other proteins histone deacetylase 2 (PfHda2) [ 60 ] and heterochromatin protein 1 (PfHP1) [ 61 , 62 ], epigenetically regulate AP2-G, preventing its expression in asexual parasites. Another protein, gametocyte development 1 (GDV1), releases derepression and activates ap2-g by eviction of HP1 [ 63 ].…”