# Epigenetic reprogramming of the malaria parasite

> **NIH NIH R21** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $204,583

## Abstract

Plasmodium falciparum (Pf) is the most lethal of the five species of malaria affecting 3.4 billion humans
annually. The Pf life cycle consists of a single round of sexual and asexual replication in the mosquito gut and
human liver, respectively, followed by multiple rounds of asexual replication in human red blood cells (RBCs).
Proper transcriptional regulation at each stage is essential for the successful completion of the life cycle, for
gametocytogenesis and for RBC invasion. Epigenetic enzymes are thought to play important and potentially
essential roles in this regulation. The methylation state of histones at specific genomic loci, for example,
controls the expression of stage-specific transcription factors such as AP2-G, of nutrient uptake channels
including the Clag3 gene paralogs, and of mono-allelically expressed multi-gene families such as the highly
virulent var genes that encode adhesion proteins involved in antigenic variation. These loci are kept
transcriptionally repressed by trimethylation of lysine 9 on histone 3 (H3K9me3). Proper temporal activation of
these loci or switching to a distinct gene form for antigenic variation requires the enzymatic removal of this
H3K9me3 transcriptional silencing mark. Similarly, proper temporal repression of active genes marked by
H3K4me3 such as transcriptionally active stage-specific genes or mono-allelic loci for gene switching, requires
erasing the activating H3K4me3 mark. Demethylation of trimethylated histones such as H3K9me3 or H3K4me3
can only be carried out by Jumonji domain containing histone hydroxylases. No other proteins with this activity
are known in biology to date. The Pf genome encodes three Jumonji hydroxylases: PfJmjC1, PfJmjC2 and
PfJmj3. We propose that the aggregate activity of these enzymes is essential to Pf viability. We have a long
standing interest in defining and pharmacologically modulating Jumonji enzyme function. Our Specific Aims
here are:
Aim 1: To characterize the anti-malaria mechanism of action of three potent & selective novel Jumonji
demethylase inhibitors we have identified in an anti-malaria screen
Aim 2: To determine the function of the three putative malaria Jumonji histone demethylases (focusing
on PfJmj3 whose function has never been studied)
This proposal will establish links between the molecular players driving malaria epigenetic pathways and
events that cause pathology and immune evasion in humans, and will create a novel therapeutic pipeline of
potential anti-malarial compounds targeting putative parasite Jumonji domain-containing epigenetic enzymes.

## Key facts

- **NIH application ID:** 10086376
- **Project number:** 5R21AI139408-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** ELISABETH D MARTINEZ
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $204,583
- **Award type:** 5
- **Project period:** 2020-01-17 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10086376

## Citation

> US National Institutes of Health, RePORTER application 10086376, Epigenetic reprogramming of the malaria parasite (5R21AI139408-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10086376. Licensed CC0.

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