Lactylated histones mark virulence gene families in the malaria parasite <i>Plasmodium falciparum</i>

<jats:title>Abstract</jats:title> <jats:p> Epigenetic pathways have many important roles controlling virulence in human malaria parasites. Histone acetylation and methylation have been closely studied in this context but the novel epigenetic mark of lactylation has not yet been examined. Here, for the first time, we profiled lactyl-histone marks across the <jats:italic>P. falciparum</jats:italic> genome and found them strongly enriched at virulence genes, including genes involved in cytoadhesion and other host-cell remodelling functions. Many genes were dynamically and inducibly lactylated across the cell cycle. Thus, <jats:italic>P. falciparum</jats:italic> could use histone lactylation to control its virulence pathways in response to the prevailing metabolic environment in its host. We extended our chromatin profiling to parasites isolated directly from human patients, showing that here too, virulence gene families were strongly lactylated. This represents the first comprehensive profiling of <jats:italic>P. falciparum</jats:italic> chromatin from parasites in sub-millilitre blood samples, opening up exciting new avenues to study parasite chromatin across human disease states. </jats:p>