GDV1 induces sexual commitment of malaria parasites by antagonizing HP1-dependent gene silencing

Abstract

Malaria is caused by parasites that proliferate in the bloodstream. During each replication cycle, some parasites differentiate into gametocytes, the only forms able to infect the mosquito vector and transmit malaria. Sexual commitment is triggered by activation of AP2-G, the master transcriptional regulator of gametocytogenesis. Heterochromatin protein 1 (HP1)-dependent silencing of prevents sexual conversion in proliferating parasites. In this study, we identified gametocyte development 1 (GDV1) as an upstream activator of sexual commitment. We found that GDV1 targeted heterochromatin and triggered HP1 eviction, thus derepressing Expression of GDV1 was responsive to environmental triggers of sexual conversion and controlled via a antisense RNA. Hence, GDV1 appears to act as an effector protein that induces sexual differentiation by antagonizing HP1-dependent gene silencing.

Sex in Plasmodium falciparum: Silence Play between GDV1 and HP1

“…When Filarsky et al . [6] generated an asgdv1 knockout in the F12 line, they observed almost identical changes in gene expression as those resulting from ectopic gdv1 expression, confirming that this antisense transcript is a negative regulator of GDV1 expression. How this antisense transcript transduces the environmental signals that promote sexual commitment remains unanswered (Figure 1).…”

“…[6] dissected the function of GDV1 in P. falciparum using elegant and complementary methodologies, including conditional CRISPR-Cas9 gene editing and ChIP-seq experiments. The authors showed that GDV1 evicts HP1 from H3K9me3 sites in the parasite genome, thereby depressing AP2-G expression and inducing gametocytogenesis.…”

“…[6] show that GDV1 binds HP1, both in vivo and in vitro , through reciprocal immunoprecipitation and cellular colocalization studies, suggesting that they form a regulatory complex that functions to activate gametocytogenesis. Using an FKBP/Shield-1 conditional expression system, the authors revealed that GDV1 expression titrates sexual commitment and gametocytogenesis.…”

“…Additional microarray analysis [6] confirmed that, following ectopic expression of GDV1, AP2-G expression is immediately and significantly upregulated, and that other markers of gametocytogenesis were also differentially regulated. In the F12 parasite line, which has a loss-of-function mutation in ap2g , no downstream effectors were affected (even though AP2-G protein is still upregulated).…”

“…In the F12 parasite line, which has a loss-of-function mutation in ap2g , no downstream effectors were affected (even though AP2-G protein is still upregulated). In addition to AP2-G, eight other genes, not under the control of AP2-G, were upregulated in response to GDV1 expression in the F12 line, all of which are known to be marked by HP1 [6]. This result, combined with the upregulation of AP2-G, suggests that GDV1 activates sexual commitment by antagonizing HP1-dependent silencing of the AP2-G gene.…”