Female‐specific gene regulation in malaria parasites by an AP2‐family transcription factor

Abstract

Summary The malaria gametocyte, the gamete precursor, is the essential stage for malaria transmission to the mosquito vector. In the vertebrate host's blood, it develops into a mature male or female capable of transforming into a gamete in the mosquito blood meal. Despite the importance of this stage in the malaria life cycle, the genetic regulation of gametocyte development is poorly understood. In particular, transcription factors involved in sex‐specific gene expression have not been identified. In this paper, we report that an AP2‐family transcription factor, AP2‐FG, is responsible for female‐specific gene regulation. AP2‐FG expression in Plasmodium berghei was observed exclusively in female gametocytes, in the beginning of 4–6 h before sexual dimorphism manifests in developing gametocytes. AP2‐FG disruption resulted in the arrest of female maturation, but did not affect the development of males. Chromatin immunoprecipitation sequencing analysis suggested that AP2‐FG directly regulates over 700 genes. Its targets include genes for female gametocyte‐specific functions, such as gametogenesis, fertilization and zygote development. AP2‐FG binding to target gene promoters was associated with a 10 bp sequence motif. These results indicate that AP2‐FG plays a role in the differentiation of early gametocytes to mature females by governing a female‐specific gene expression repertoire.

Hierarchical transcriptional control regulates Plasmodium falciparum sexual differentiation

“…The second apiap2 transcript increased in abundance, is pf3d7_1317200, the P. falciparum ortholog of pbap2-g3, coexpressed with 21 genes involved in cell cycle processes, including DNA replication (GO:0044786, P = 0.0061) and chromosome organization (GO:0051276 P = 0.0046). Unlike its ortholog in P. berghei [70], no enrichment for female specific proteins or transcripts were observed in the co-expressed genes and further phenotypic information is needed to describe this ApiAP2's activity in P. falciparum. The two final ApiAP2 transcription factors are increased between stage I-V of development, with the first, pf3d7_0934400, showing mostly negative co-expression with its target genes (27/37 transcripts, including pkg and ptex88 (pf3d7_ 1105600)), suggesting this ApiAP2 transcription factor might also act as repressor.…”

“…Thereafter, three transcription factors pf3d7_ 1408200, pf3d7_1317200 and pf3d7_0611200 were increased during stage I to III of development (days 2-6). In the rodent-infectious malaria parasites P. berghei and P. yoelii, orthologs of the first two genes have been associated with gametocyte development through knockout studies [21,30,70] while little is known of pf3d7_0611200. The transcription factors were also probed for regulatory activity using coexpression analysis by GRENITS.…”

Plasmodium sexual differentiation: how to make a female

“…Whatever the route to male‐female differentiation, the observation that parasites that lack AP2‐FG still initiate female commitment and start expressing female‐specific markers (Yuda et al , ) indicates that AP2‐FG is not itself the switch that determines female sex, but rather part of a regulatory cascade that is initiated by other factors that precede AP2‐FG. So far, AP2‐G is the only known ApiAP2 transcription factor that operates as a developmental switch, whereas other members of the ApiAP2 family, including AP2‐FG, regulate the expression of specific genes as part of a regulatory cascade.…”

“…Working with the murine malaria parasite Plasmodium berghei , Yuda and colleagues shed some light on the mechanism of female gametocyte development with the description of an ApiAP2 transcription factor previously named AP2‐G3 and here referred to as AP2‐FG (FG stands for female gametocyte) (Yuda et al , ). They show that this transcription factor is expressed specifically in female gametocytes.…”

“…In support of this view, disruption of AP2‐FG results in reduced expression of a number of female‐transcribed genes, and Chip‐Seq analyses show that this protein binds preferentially to the regulatory region of genes involved in various processes in female gametocyte biology. Binding appears to occur via a newly identified 10 bp motif (Yuda and colleagues, ). Altogether, Yuda and colleagues provide compelling evidence for the first clear identification of a transcription factor that regulates sex‐specific expression.…”