# Mechanisms Governing Expression of AP2-G, the Master Regulator of Sexual Differentiation in Malaria Parasites

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $45,520

## Abstract

Project Summary/Abstract
 For Plasmodium falciparum, the most widespread and virulent human malaria parasite, persistence within the
 human host requires asexual replication within red blood cells, while transmission depends on differentiation to
 non-replicative sexual stages, gametocytes. At the time of invasion parasites are already committed to one of
 these fates, with the developmental decision having been made in the previous cell cycle. Sexual commitment
 requires two proteins: AP2-G and GDV1. Expression of AP2-G, the transcriptional master regulator of sexual
 development, during this “commitment cycle” poises gene expression to initiate sexual development upon re-
 invasion. Derepression of the epigenetically silenced ap2-g locus through a heretofore-unknown mechanism
 leads to transcription activation of ap2-g and subsequent sexual commitment of newly forming parasites.
 Unlike AP2-G, GDV1 is expressed in every replication cycle. However, previous work showed that this protein
 localizes to the nuclear periphery in a subpopulation of committed parasites, an ideal position for regulation of
 epigenetically silenced genes, including ap2-g. RNA microarray data suggests that the timing of maximal
 GDV1 expression coincides with initial ap2-g transcription. These data suggest that GDV1 may play a role in
 activation of ap2-g transcription. This activation may be facilitated by interaction with key upstream regulatory
 elements. In the proposed study, I will investigate mechanisms of ap2-g activation using two complementary
 strategies by identifying the key upstream sequence elements of ap2-g that are necessary and sufficient for its
 silencing and transcriptional activation (AIM 1) and defining the role of GDV1 in ap2-g activation (AIM 2).
 The first question to be addressed regards the specific roles of upstream regulatory elements in
 activating or silencing transcription of ap2-g. We address this by first identifying the transcriptional start site
 (TSS) of ap2-g at different stages of parasite development using 5’ RACE. Secondly we will create a system
 for integrative recombination that will allow for rapid modification of upstream sequence elements in the
 endogenous ap2-g locus. qRT-PCR, immunofluorescence, and gametocyte formation will be used to monitor
 affects on ap2-g activation with each TSS and following upstream modification of the locus. The next question
 to be addressed focuses on the necessity of GDV1 and its nuclear localization for transcriptional activation of
 ap2-g. To address this, a system for conditional misloclaization of GDV1 will be engineered allowing for precise
post-translational regulation of the protein. ap2-g activation will be measured using qRT-PCR,
 immunofluorescence and gametocyte formation. Furthermore, nuclear localization of GDV1 as well as direct
 interaction of the protein with the ap2-g locus will be analyzed using combined IFA/FISH and GDV1 ChIP.
 Successful completion of this work will yield...

## Key facts

- **NIH application ID:** 9962284
- **Project number:** 5F31AI136405-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Chantal Harris
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2018-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962284

## Citation

> US National Institutes of Health, RePORTER application 9962284, Mechanisms Governing Expression of AP2-G, the Master Regulator of Sexual Differentiation in Malaria Parasites (5F31AI136405-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9962284. Licensed CC0.

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