AP2-HS and a GDV1 regulatory feedback loop mediate environmental induction of sexual conversion in Plasmodium falciparum.

Human-to-mosquito transmission of the malaria parasite Plasmodium falciparum requires conversion of some parasites to gametocytes, a non-replicative sexual form. Specific conditions of the human blood environment that induce parasite stress increase sexual conversion rates. Sexual conversion is triggered by the transcription factor AP2-G and its upstream activator, GDV1. However, the molecular mechanisms underlying environmentally induced sexual conversion are unclear. Here we show that environmental induction of gdv1 expression and sexual conversion requires the transcription factor AP2-HS, which plays a dual role as activator or repressor in different pathways. Activation of gdv1 expression, either spontaneously or in response to environmental conditions, triggers a positive-negative regulatory feedback loop between GDV1 and its antisense long non-coding RNA (gdv1-as) repressor. This involves GDV1-dependent displacement of heterochromatin from the gdv1-as promoter. Our results describe a complex regulatory mechanism enabling P. falciparum to adjust its investment in transmission under different stress conditions.