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 TraF, 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 TraF 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 TraF, 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. HighlightsO_LIzld mRNA is repressed by microRNAs in XY somatic gonadal cells C_LIO_LIZld is upregulated in and required for sex reversal of XY chinmo-/- cells C_LIO_LIZld induces Qkr58E-2 and EcR, which cause TraF and female-biased transcription C_LIO_LIZld feminizes XY adipose cells by inducing TraF and downregulating Chinmo C_LI