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Role of chromatin modifiers in the transcription dynamics of virulence factors of the human malaria parasite Plasmodium falciparum

Grant number: 17/24267-7
Support type:Regular Research Grants
Duration: May 01, 2018 - April 30, 2020
Field of knowledge:Biological Sciences - Parasitology
Principal Investigator:Gerhard Wunderlich
Grantee:Gerhard Wunderlich
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Assoc. researchers:Paulo Eduardo Martins Ribolla ; Wesley Luzetti Fotoran


Malaria parasites strictly control gene expression in each phase of their complex life cycle, depending on the host environment. The control of expression is mostly at the transcriptional level, although post-translational mechanisms are also encountered (e.g. P-bodies). Transcriptional control is exerted by dynamic chromatin modification and the deliberate inhibition of chromatin modifiers may seriously interfere with or kill parasites. In this project, we focus on the role and importance of chromatin modifiers on variant gene transcription in blood stage Plasmodium falciparum parasites, which cause the most dangerous form of human malaria. These parasites are also still endemic in the Brazilian Amazon. In a previous study, we have created transgenic parasite lines which permit functional characterization (via ribozymes) of chromatin modifiers. Introducing also a hemagglutinine tag, we generated mutants in chromatin modifier genes of histone deactylases (SIR2A), histone demthylases (Jumonji-like demethylase 1, 2 and lysine histone demethylase 1, LSD-1). We also modified a DNA Cytosine methyltransferase, a acetyl histone transferase (SET2) and an AcetylCoA synthetase, which probably delivers acetyl rests for Acetyl histone transferases. We also modified three putative transcription factors of the ApiAP2 family which may be involved in variant gene transcription. Variant (var) genes encode adhesins which then may lead to severe malaria outcomes. We propose to elucidate by ChIPseq the chromosomal sites/genes in which the modified factors associate. Via the hemagglutinine tag, we will analyze which proteins coprecipitate with the modified proteins, using mass spec. Further, we propose to analyze coprecipitating (nc)RNAs which may play a decisive role in orchestrating the variegated transcription in the case of variant gene family transcription. The expected results will contribute to the understanding of the coordinating network that underlies gene transcription in blood stage malaria parasites, possibly revealing novel attack points for drugs. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FOTORAN, WESLEY L.; MUENTEFERING, THOMAS; KLEIBER, NICOLE; MIRANDA, BEATRIZ N. M.; LIEBAU, EVA; IRVINE, DARRELL J.; WUNDERLICH, GERHARD. A multilamellar nanoliposome stabilized by interlayer hydrogen bonds increases antimalarial drug efficacy. Nanomedicine-Nanotechnology Biology and Medicine, v. 22, NOV 2019. Web of Science Citations: 0.

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