bioRxiv | 2019
Polycomb suppresses a female gene regulatory network in Sertoli cells
Abstract
Gonadal sex determination is controlled by the support cells of testes and ovaries. Sexual fate becomes labile and interchangeable with the removal of specific, critical transcription factors from postnatal gonad support cells. In Sertoli cells, the specific support cells for postnatal testes, the epigenetic mechanism that maintains cellular memory to suppress female sexual differentiation remains unknown. Here, we show that, in postnatal Sertoli cells, Polycomb suppresses a female gene regulatory network. Through genetic ablation, we removed Polycomb repressive complex 1 (PRC1) from embryonic Sertoli cells after sex determination. PRC1-depleted postnatal Sertoli cells exhibited defective proliferation and cell death, leading to the degeneration of adult testes. In adult Sertoli cells, PRC1 suppressed the specific, critical genes required for granulosa cells, the support cells of ovaries, thereby inactivating the female gene regulatory network. The underlying chromatin of female genes was coated with Polycomb-mediated repressive modifications: PRC1-mediated H2AK119ub and PRC2-mediated H3K27me3. Taken together, we identify a critical mechanism centered on Polycomb that maintains the male fate in adult testes. Significance Sex differences in mammals are defined by the reproductive organs, testes and ovaries. In testes and ovaries, sexual fate is determined by Sertoli cells and granulosa cells, respectively, which are supporting cells derived from common somatic progenitors. Critical transcription factors determine sexual fate of Sertoli and granulosa cells, and, remarkably, removal of these factors reverses sexual identity. Therefore, sexual fate is surprisingly plastic. Here we address a long-standing question in developmental biology of how male sexual fate is maintained in testes throughout life. We show that epigenetic machinery of Polycomb repressive complex 1 (PRC1) suppresses a female gene regulatory network in Sertoli cells. Thus, Polycomb preserves cellular memory and sexual identity of Sertoli cells, thereby defining the testicular fate.