title: Global transcriptional repression: An initial and essential step for Plasmodium sexual development.
abstract: Gametocytes are nonreplicative sexual forms that mediate malaria transmission to a mosquito vector. They are generated from asexual blood-stage parasites that proliferate in the circulation. However, little is known about how this transition is genetically regulated. Here, we report that an Apetala2 (AP2) family transcription factor, AP2-G2, regulates this transition as a transcriptional repressor. Disruption of AP2-G2 in the rodent malaria parasite Plasmodium berghei did not prevent commitment to the sexual stage but did halt development before the appearance of sex-specific morphologies. ChIP-seq analysis revealed that AP2-G2 targeted ∼1,500 genes and recognized a five-base motif in their promoters. Most of these target genes are required for asexual proliferation of the parasites in the blood, suggesting that AP2-G2 blocks the program that precedes asexual replication to promote conversion to the sexual stage. Microarray analysis showed that the identified targets constituted ∼70% of the up-regulated genes in AP2-G2-depleted parasites, suggesting that AP2-G2 actually functions as a repressor in gametocytes. A promoter assay using a centromere plasmid demonstrated that the binding motif functions as a cis-acting negative regulatory element. These results suggest that global transcriptional repression, which occurs during the initial phase of gametocytogenesis, is an essential step in Plasmodium sexual development.
authors.affiliation: Department of Medical Zoology, Mie University School of Medicine, Mie, Tsu 514-0001, Japan m-yuda@doc.medic.mie-u.ac.jp.
authors.forename: Masao
authors.initials: M
authors.lastname: Yuda
authors.affiliation: Department of Medical Zoology, Mie University School of Medicine, Mie, Tsu 514-0001, Japan.
authors.forename: Shiroh
authors.initials: S
authors.lastname: Iwanaga
authors.affiliation: Department of Medical Zoology, Mie University School of Medicine, Mie, Tsu 514-0001, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Kaneko
authors.affiliation: Department of Medical Zoology, Mie University School of Medicine, Mie, Tsu 514-0001, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kato
mesh_terms: D000818:Animals; D005260:Female; D008018:Life Cycle Stages / Q000502:physiology*; D008288:Malaria / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010962:Plasmodium berghei / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D015800:Protozoan Proteins; D014157:Transcription Factors
keywords: gametocytogenesis; malaria; sexual development; transcription factor