Epigenetic and Epitranscriptomic Gene Regulation in <i>Plasmodium falciparum</i> and How We Can Use It against Malaria.

Malaria, caused by <i>Plasmodium</i> parasites, is still one of the biggest global health challenges. <i>P. falciparum</i> is the deadliest species to humans. In this review, we discuss how this parasite develops and adapts to the complex and heterogenous environments of its two hosts thanks to varied chromatin-associated and epigenetic mechanisms. First, one small family of transcription factors, the ApiAP2 proteins, functions as master regulators of spatio-temporal patterns of gene expression through the parasite life cycle. In addition, chromatin plasticity determines variable parasite cell phenotypes that link to parasite growth, virulence and transmission, enabling parasite adaptation within host conditions. In recent years, epitranscriptomics is emerging as a new regulatory layer of gene expression. We present evidence of the variety of tRNA and mRNA modifications that are being characterized in <i>Plasmodium</i> spp., and the dynamic changes in their abundance during parasite development and cell fate. We end up outlining that new biological systems, like the mosquito model, to decipher the unknowns about epigenetic mechanisms in vivo; and novel methodologies, to study the function of RNA modifications; are needed to discover the Achilles heel of the parasite. With this new knowledge, future strategies manipulating the epigenetics and epitranscriptomic machinery of the parasite have the potential of providing new weapons against malaria.