Histone lactylation: a novel epigenetic feature in malaria parasites

The proposed research will investigate an entirely novel aspect of the biology of the human malaria parasite, Plasmodium. Epigenetic marks such as histone acetylation and methylation play important roles in the biology and virulence of this parasite. I propose to study a new epigenetic modification, histone lactylation, which was recently discovered in human cells, where it can promote gene expression. I have shown that the mark is present in Plasmodium as well. Lactyl epigenetic marks could be particularly important in Plasmodium because malaria parasites are exposed to high and fluctuating lactate levels in their human host environment, and hyperlactataemia is characteristic of severe malarial disease. This project will fully characterise the spectrum of histone lactylation in Plasmodium and assess its sensitivity to varying levels of exogenous lactate. It will map the presence of histone lactylation throughout the genome, and identify the enzymes responsible. It will then explore the idea that histone lactylation could modulate parasite virulence and stress resistance in vivo, using isolates obtained directly from African malaria patients as well as laboratory lines. The research will significantly improve our understanding of an entirely novel epigenetic mark, which may affect virulence in a very important human pathogen.