Research projects

Epigenetic control of virulence proteins expression in Plasmodium spp.

The P. falciparum expresses and exports highly variable proteins on the surface of infected RBC for cytoadherence. The parasite changes its variable protein in response to host immunity. The variable proteins are encoded by a multigene family (~60 genes), and located in the sub-telomeric regions across all 14 chromosomes. It expresses one var gene at the time of infection and maintains the remaining 59 var genes in a suppressed state. The gene suppressor mechanism is achieved through clustering of var genes to the nuclear periphery. It has been shown that H3K36me3 is highly enriched in repressor clusters, however, the mechanisms by which the H3K36me3 methyl mark is propagated, and forms suppressor var gene clusters to the nuclear periphery are unknown. We have identified PHD domain that binds strongly to methylmarks and allosterically stimulates the enzyme activity to propagate H3K36me3 methyl marks and clusters var genes into the nuclear periphery (BBA Gene Regulatory Mechanisms, 2021). In addition, we have identified the CHROMO domain that binds to the H3K9me3 mark and such interaction in parasites mediates the suppression of subsets of the second family of virulence genes i.e RIFINs (J Mol Biol, 2022). A detailed study on this line would pave way for better vaccine designs against malaria.

Molecular basis of Exportome regulation in Plasmodium spp to remodel the iRBCs

We have identified epigenetic methyl marks at unconventional sites on core histones of P. falciparum. Interestingly, all these methylation sites are located at the core histone on the lateral surface of the nucleosome and reside very proximal to the DNA contact point on histones. We characterized the H3K64me3 mark and found it highly dynamic on the chromatin, enriched in the ring, and trophozoite stages, and reduced in the multinucleated schizont stage. This is the first report to show the dynamic deposition of the histone methylation marks in various developmental stages of P. falciparum. We have done a detailed characterization of the H3K64me3 mark and have identified the PfSET4 and PfSET5 enzymes of P. falciparum specifically methylate at H3K64. The global ChIP sequencing analysis has revealed that the stage-specific dynamic distribution of H3K64me3 regulates the exportome family proteins in Plasmodium spp. This is the first molecular evidence that shows the direct role of epigenetic players in stage-specific gene expressions (J Biol Chem, 2021).

RNA methylation: A check point translational plasticity in Apicomplexan parasites

The Plasmodium spp. shows discrepancy in the mRNA levels and delay in protein synthesis during its asexual development in RBCs. We hypothesized that post-transcriptional modifications of mRNA and tRNA could regulate the differential protein synthesis in various developmental stages. We have identified the presence of methylation at the C38 position of tRNA Asp in P. falciparum (BBA Gene Regulatory Mechanisms, 2017). In addition, we have reported that m6A modifications in mRNA of P. falciparum are recognized by YTH protein and such interaction regulates the translation in the malaria parasite. Apparently, this is the first report on YTH protein in any protozoan parasites (Epigenetics & Chromatin, 2020; mBio, 2021). Currently, we investigate the functions of various modifications on the RNA of human malaria parasites and their role in parasite virulence.