Metabolic competition between lipid metabolism and histone methylation regulates sexual differentiation in human malaria parasites.

Abstract

For Plasmodium falciparum, the most widespread and virulent human malaria parasite, persistence depends on continuous asexual replication in red blood cells, while transmission requires their differentiation into non-replicating gametocytes that can infect the mosquito vector. This decision is controlled by stochastic derepression of a heterochromatin-silenced locus encoding PfAP2-G, the master transcription factor of sexual differentiation. The frequency of pfap2-g derepression was shown to be responsive to extracellular phospholipid precursors but the mechanism linking these metabolites to epigenetic regulation of pfap2-g was unknown. Here we show that this response is mediated by metabolic competition for S-adenosylmethionine between histone methyltransferases and phosphoethanolamine methyltransferase, a critical enzyme in the parasite's pathway for de novo phosphatidylcholine synthesis. When phosphatidylcholine precursors are scarce, increased consumption of SAM for de novo phosphatidylcholine synthesis impairs maintenance of the histone methylation responsible for silencing pfap2-g, increasing the frequency of derepression and sexual differentiation.