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

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...

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Autores principales:	Mukul Rawat, Abhishek Kanyal, Aishwarya Sahasrabudhe, Shruthi Sridhar Vembar, Jose-Juan Lopez-Rubio, Krishanpal Karmodiya
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f714722b9378468596438180022cd502
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spelling	oai:doaj.org-article:f714722b9378468596438180022cd5022021-12-02T14:12:08ZHistone acetyltransferase PfGCN5 regulates stress responsive and artemisinin resistance related genes in Plasmodium falciparum10.1038/s41598-020-79539-w2045-2322https://doaj.org/article/f714722b9378468596438180022cd5022021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79539-whttps://doaj.org/toc/2045-2322Abstract 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.Mukul RawatAbhishek KanyalAishwarya SahasrabudheShruthi Sridhar VembarJose-Juan Lopez-RubioKrishanpal KarmodiyaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mukul Rawat Abhishek Kanyal Aishwarya Sahasrabudhe Shruthi Sridhar Vembar Jose-Juan Lopez-Rubio Krishanpal Karmodiya Histone acetyltransferase PfGCN5 regulates stress responsive and artemisinin resistance related genes in Plasmodium falciparum
description	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.
format	article
author	Mukul Rawat Abhishek Kanyal Aishwarya Sahasrabudhe Shruthi Sridhar Vembar Jose-Juan Lopez-Rubio Krishanpal Karmodiya
author_facet	Mukul Rawat Abhishek Kanyal Aishwarya Sahasrabudhe Shruthi Sridhar Vembar Jose-Juan Lopez-Rubio Krishanpal Karmodiya
author_sort	Mukul Rawat
title	Histone acetyltransferase PfGCN5 regulates stress responsive and artemisinin resistance related genes in Plasmodium falciparum
title_short	Histone acetyltransferase PfGCN5 regulates stress responsive and artemisinin resistance related genes in Plasmodium falciparum
title_full	Histone acetyltransferase PfGCN5 regulates stress responsive and artemisinin resistance related genes in Plasmodium falciparum
title_fullStr	Histone acetyltransferase PfGCN5 regulates stress responsive and artemisinin resistance related genes in Plasmodium falciparum
title_full_unstemmed	Histone acetyltransferase PfGCN5 regulates stress responsive and artemisinin resistance related genes in Plasmodium falciparum
title_sort	histone acetyltransferase pfgcn5 regulates stress responsive and artemisinin resistance related genes in plasmodium falciparum
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f714722b9378468596438180022cd502
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Histone acetyltransferase PfGCN5 regulates stress responsive and artemisinin resistance related genes in Plasmodium falciparum

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