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A novel DNA-binding protein regulates sexual differentiation in malaria parasites and is essential for transmission

Transmission of Plasmodium falciparum and other malaria parasites requires their differentiation from asexual blood stages into gametocytes, the non-replicative sexual stage necessary for transmission to the mosquito vector. This transition involves changes in gene expression and chromatin reorganization mediating the activation and silencing of stage-specific genes. However, the genomes of malaria parasites have been noted for their dearth of transcriptional and chromatin regulators and the molecular mediators of these changes remain largely unknown. We recently identified HomeoDomain Protein 1 (HDP1) as a novel chromatin-associated DNA-binding protein that drives changes in chromatin structure and gene expression during early sexual differentiation. The discovery of a homeodomain-like DNA-binding protein marks a new class of transcriptional regulator in malaria parasites outside of the better-characterized ApiAP2 family. In this study, we demonstrate that HDP1 is required for gametocyte maturation and parasite transmission by facilitating the necessary upregulation of inner membrane complex components in early gametocytes.