title: A transcriptional switch underlies commitment to sexual development in malaria parasites.
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.
authors.affiliation: 1] Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA [2] Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA (B.F.C.K.); Department of Molecular Biology and Center for Infectious Disease Dynamics, The Pennsylvania State University, State College, Pennsylvania 16802, USA (V.M.C., M.L.).
authors.forename: Björn F C
authors.initials: BF
authors.lastname: Kafsack
authors.affiliation: 1] Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Barcelona, 08036 Catalonia, Spain [2] Institute for Research in Biomedicine (IRB), Barcelona, 08028 Catalonia, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Rovira-Graells
authors.affiliation: 1] Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK [2] Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK.
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.affiliation: Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Barcelona, 08036 Catalonia, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bancells
authors.affiliation: 1] Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA [2] Institute for Research in Biomedicine (IRB), Barcelona, 08028 Catalonia, Spain [3] Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA (B.F.C.K.); Department of Molecular Biology and Center for Infectious Disease Dynamics, The Pennsylvania State University, State College, Pennsylvania 16802, USA (V.M.C., M.L.).
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Crowley
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Susana G
authors.initials: SG
authors.lastname: Campino
authors.affiliation: Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
authors.forename: April E
authors.initials: AE
authors.lastname: Williams
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Drought
authors.affiliation: 1] Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK [2] Wellcome Trust Sanger Centre for Human Genetics, Oxford OX3 7BN, UK.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London WC1E 7HT, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Baker
authors.affiliation: 1] Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Barcelona, 08036 Catalonia, Spain [2] Institute for Research in Biomedicine (IRB), Barcelona, 08028 Catalonia, Spain [3] Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, 08010 Catalonia, Spain.
authors.forename: Alfred
authors.initials: A
authors.lastname: Cortés
authors.affiliation: 1] Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA [2] Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA [3] Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA (B.F.C.K.); Department of Molecular Biology and Center for Infectious Disease Dynamics, The Pennsylvania State University, State College, Pennsylvania 16802, USA (V.M.C., M.L.).
authors.forename: Manuel
authors.initials: M
authors.lastname: Llinás
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D020868:Gene Silencing; D017125:Genes, Protozoan / Q000235:genetics; D018503:Genome, Protozoan / Q000235:genetics; D005854:Germ Cells / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D008288:Malaria / Q000469:parasitology*; D008297:Male; D010271:Parasites / Q000166:cytology / Q000235:genetics / Q000502:physiology*; D010963:Plasmodium falciparum / Q000166:cytology / Q000235:genetics* / Q000502:physiology; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D012100:Reproduction, Asexual; D012733:Sex Differentiation / Q000235:genetics; D046468:Sexual Development / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D015800:Protozoan Proteins