Histone acetyltransferase PfGCN5 regulates stress responsive and artemisinin resistance related genes in Plasmodium falciparum

Mukul Rawat,Krishanpal Karmodiya,Shruthi Sridhar Vembar,Abhishek Kanyal,Aishwarya Sahasrabudhe,Jose-Juan Lopez-Rubio

doi:10.1038/s41598-020-79539-w

Abstract

Plasmodium falciparum has evolved resistance to almost all front-line drugs including artemisinin, which threatens malaria control and elimination strategies. Oxidative stress and protein damage responses have emerged as key players in the generation of artemisinin resistance. In this study, we show that PfGCN5, a histone acetyltransferase, binds to the stress-responsive genes in a poised state and regulates their expression under stress conditions. Furthermore, we show that upon artemisinin exposure, genome-wide binding sites for PfGCN5 are increased and it is directly associated with the genes implicated in artemisinin resistance generation like BiP and TRiC chaperone. Interestingly, expression of genes bound by PfGCN5 was found to be upregulated during stress conditions. Moreover, inhibition of PfGCN5 in artemisinin-resistant parasites increases the sensitivity of the parasites to artemisinin treatment indicating its role in drug resistance generation. Together, these findings elucidate the role of PfGCN5 as a global chromatin regulator of stress-responses with a potential role in modulating artemisinin drug resistance and identify PfGCN5 as an important target against artemisinin-resistant parasites.

Highlights

Plasmodium falciparum has evolved resistance to almost all front-line drugs including artemisinin, which threatens malaria control and elimination strategies
With the help of chromatin immunoprecipitation coupled high-throughput sequencing (ChIP-seq) and transcriptomic (RNA-sequencing) analyses, we show that PfGCN5 activates genes that are important for the maintenance of parasite cellular homeostasis during various stress conditions
The differences in fragment pattern between the two antibodies can be attributed to the fact that the previous study has used an antiserum recognizing the C-terminal region of the PfGCN5 as compared to the N-terminal PfGCN5 antibody generated in this study

Summary

Introduction

Plasmodium falciparum has evolved resistance to almost all front-line drugs including artemisinin, which threatens malaria control and elimination strategies. With the help of chromatin immunoprecipitation coupled high-throughput sequencing (ChIP-seq) and transcriptomic (RNA-sequencing) analyses, we show that PfGCN5 activates genes that are important for the maintenance of parasite cellular homeostasis during various stress conditions. Our data identify histone acetyltransferase, PfGCN5 as a key chromatin regulator of stress responsive genes and reveals its important role in emergence of artemisinin drug resistance.

Results

Conclusion