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

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.