P. falciparum can cytoadhere onto the endothelial vessels by using a parasite-coded PfEMP1 ligand on the surface of the RBCs. This prevents the clearance of the parasite from the bloodstream by the spleen. This protein is encoded by a cluster of genes called var genes. There are a total of 60 var genes encoded by parasite, of which only one var gene is expressed; the rest, 59 var genes, are epigenetically suppressed. Since the var gene product PfEMP is exposed onto the surface of the RBC, it gets targeted by the immune system, where the var genes are known to undergo spontaneous switching, resulting in a different variant of PfEMP1 being expressed on the surface of the red blood cell. This creates a major hurdle to creating an effective vaccine against P. falciparum. PfSET2 is known to cause trimethylations at H3K36, which are associated with the suppression of all var genes. The regulation mechanism of var gene switching in response to host immunity is unknown. Previous studies from our lab have shown that the PHD3 domain of PfSET2 interacts with the H3K36me2 mark and stimulates the activity of the SET2 domain. We will investigate the role of allosteric-stimulated PfSET2 protein-mediated propagation of the H3K36me3 mark on the var genes and mutually exclusive expression of single var genes in P. falciparum. Overall, this study may identify novel mechanisms of antigenic variation processes in human malaria parasite.