The pioneer factor Zelda induces male-to-female somatic sex reversal in adult tissues

Abstract

Somatic sex identity must be maintained throughout adulthood for tissue function. Adult somatic stem cells in the Drosophila testis (i.e., CySCs) lacking the transcription factor Chinmo are reprogrammed to their ovarian counterparts by induction of female-specific Tra ^F , but this is not mechanistically understood. Pioneer factors play central roles in direct reprogramming, and many upregulated genes in chinmo ^-/- CySCs contain binding sites for the pioneer factor Zelda (Zld). microRNAs repress zld mRNA in wild type CySCs, but they are downregulated after Chinmo loss, allowing for zld mRNA translation. Zld depletion from chinmo ^-/- CySCs suppresses feminization, and ectopic Zld induces Tra ^F and feminizes wild-type CySCs. qkr58E-2 and ecdysone receptor ( EcR ), direct Zld targets in the embryo, are female-biased in adult gonads and upregulated in chinmo ^-/- CySCs. The RNA-binding protein Qkr58E-2 produces Tra ^F , while EcR promotes female-biased gene expression. Ectopic Zld feminizes adult male adipose tissue, demonstrating that Zld can instruct female and override male identity in adult XY tissues.

Highlights: zld mRNA is repressed by microRNAs in XY somatic gonadal cells Zld is upregulated in and required for sex reversal of XY chinmo ^-/- cells Zld induces Qkr58E-2 and EcR, which cause Tra ^F and female-biased transcription Zld feminizes XY adipose cells by inducing Tra ^F and downregulating Chinmo.