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A transcriptional switch underlies commitment to sexual development in malaria parasites.

TitleA transcriptional switch underlies commitment to sexual development in malaria parasites.
Publication TypeJournal Article
Year of Publication2014
AuthorsKafsack BFC, Rovira-Graells N, Clark TG, Bancells C, Crowley VM, Campino SG, Williams AE, Drought LG, Kwiatkowski DP, Baker DA, Cortés A, Llinás M
JournalNature
Volume507
Issue7491
Pagination248-52
Date Published2014 Mar 13
ISSN1476-4687
KeywordsAnimals, DNA-Binding Proteins, Female, Gene Expression Regulation, Gene Silencing, Genes, Protozoan, Genome, Protozoan, Germ Cells, Malaria, Male, Parasites, Plasmodium falciparum, Protozoan Proteins, Reproduction, Asexual, Sex Differentiation, Sexual Development, Transcription, Genetic
Abstract

The life cycles of many parasites involve transitions between disparate host species, requiring these parasites to go through multiple developmental stages adapted to each of these specialized niches. Transmission of malaria parasites (Plasmodium spp.) from humans to the mosquito vector requires differentiation from asexual stages replicating within red blood cells into non-dividing male and female gametocytes. Although gametocytes were first described in 1880, our understanding of the molecular mechanisms involved in commitment to gametocyte formation is extremely limited, and disrupting this critical developmental transition remains a long-standing goal. Here we show that expression levels of the DNA-binding protein PfAP2-G correlate strongly with levels of gametocyte formation. Using independent forward and reverse genetics approaches, we demonstrate that PfAP2-G function is essential for parasite sexual differentiation. By combining genome-wide PfAP2-G cognate motif occurrence with global transcriptional changes resulting from PfAP2-G ablation, we identify early gametocyte genes as probable targets of PfAP2-G and show that their regulation by PfAP2-G is critical for their wild-type level expression. In the asexual blood-stage parasites pfap2-g appears to be among a set of epigenetically silenced loci prone to spontaneous activation. Stochastic activation presents a simple mechanism for a low baseline of gametocyte production. Overall, these findings identify PfAP2-G as a master regulator of sexual-stage development in malaria parasites and mark the first discovery of a transcriptional switch controlling a differentiation decision in protozoan parasites.

DOI10.1038/nature12920
Alternate JournalNature
PubMed ID24572369
PubMed Central IDPMC4040541
Grant List090532/Z/09/Z / / Wellcome Trust / United Kingdom
094752 / / Wellcome Trust / United Kingdom
P50GM071508 / GM / NIGMS NIH HHS / United States
J005398 / / Medical Research Council / United Kingdom
/ / Biotechnology and Biological Sciences Research Council / United Kingdom
G0600230 / / Medical Research Council / United Kingdom
R01 AI076276 / AI / NIAID NIH HHS / United States
098051 / / Wellcome Trust / United Kingdom
P50 GM071508 / GM / NIGMS NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
090532 / / Wellcome Trust / United Kingdom
/ / Howard Hughes Medical Institute / United States
090770 / / Wellcome Trust / United Kingdom
G0600718 / / Medical Research Council / United Kingdom

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