Plasmodium falciparum SET2 domain is allosterically regulated by its PHD-like domain to methylate at H3K36.

The antigenic variation is an essential mechanism employed by the malaria parasite to establish a chronic infection in humans. Three major virulent proteins EMP1, RIFINs, and STEVOR have been implicated in contributing to the antigenic variation process and are encoded by multigene families in Plasmodium spp. The key virulence factor PfEMP1 is encoded by var genes, and it exhibits a mutually exclusive transcriptional switching between var genes, ensuring an individual parasite only transcribes a single var gene at a time. Expression of var genes is tightly regulated by two histone epigenetic methylation marks H3K36me3 and H3K9me3, of which the H3K36me3 mark is highly enriched on transcription start sites (TSSs) of suppressed var genes in P. falciparum. However, the mechanisms of H3K36me3 mark propagation on all the 59 var genes of P. falciparum are not known. Here, we have identified a PHD (Plant Homeodomain-like Domain) like domain present within the PfSET2 protein that specifically binds to the H3K36me2 mark, an intermediate product of the H3K36me3 mark formation on the nucleosome. Surprisingly, we have found that PHD - H3K36me2 interaction leads to stimulation of SET2 domain activity on the nucleosome substrates. The allosteric stimulation of the PfSET2 domain by PHD-like domain present within the same protein suggests a novel mechanism of H3K36me3 mark propagation on var genes of P. falciparum. This study proposes allosteric regulation of PfSET2 protein by H3K36me2 mark as an essential mechanism of var genes suppression to ensure successful antigenic variation by the malaria parasite.