DOT1L regulates the dynamics of the host chromatin during host – pathogen interaction

Abstract text

Visceral Leishmaniasis ia caused by L. donovani. Existing drugs show severe side effects and drug resistance, therefore, new effective treatments against leishmaniasis are needed. In recent years, epigenetic modulators have emerged as attractive drug targets.

Mammalian DOT1L contains catalytic domain region, which can potentially methylate H3K79, which involved in cell cycle progression. However, the role of DOT1L during host pathogen interaction has not yet been delineated. Therefore, we undertook studies to explore the role of this epigenetic modulator during infection.

We have infected the differentiated THP1 macrophage cell line with leishmania and then check the mRNA level and protein level of DOT1L. We have also check the methylation activity of DOT1L as well as the protein expression of histone methylation marks after infection. Also we did the knockdown studies of DOT1L and then determine the parasitemia load. We also checked the mRNA level of defensins gene.

It been observed that the mRNA level of DOT1L increases on 6h of infection as compared to 0 hour of infection which leads to increase in protein expression of H3K79 methylation . Silencing of DOT1L decreases the methylation activity of DOT1L and so the parasitemia load indicating methylation mediated by DOT1L is required for L. donovani infection. To understand the mechanism, we analysed the expression of defensins genes in siDOT1L cells and found them to be upregulated as compared to cells transfected with scrambled RNA. Based on these results, we hypothesise that H3K79 methylation mediated DOT1L is required for downregulation of defensins gene on Leishmania infection.

So we conclude that our results indicate that DOT1L expression is required for Leishmania donovani infection and therefore, might be an potential drug target for the treatment of Leishmaniasis.