A network of steroid receptor transcription factors regulates ovarian chromatin remodelling in the transition to ovulation

Steroid receptors are transcription factors activated by progesterone (PGR), androgen (AR) and glucocorticoid (GR), with shared canonical DNA binding sequence. In the ovary, PGR is the key determinant of ovulation while AR and GR play important roles in growing follicles. However, the mechanism that defines the unique physiological roles of these conserved receptors, and whether their functions overlap remains elusive. We investigated the relationship between AR, GR and PGR during folliculogenesis and ovulation. In response to ovulatory hormones, PGR and GR jointly gained binding to novel chromatin sites and had a substantial effect on periovulatory gene regulation, whereas AR-chromatin interactions were repressed. Two modes of PGR action to drive gene activation were identified. Induction of PGR leads to cooperative PGR/GR recruitment to novel promoters, increased histone acetylation and chromatin accessibility, culminating in transcription activation, with PGR being the key component in the unique ovulatory transcriptional complex. Alternatively, PGR tethered to enhancers interacts with pre-accessible, AR/GR-bound promoters to promote gene activation. Our findings illustrate the multi-faceted ovarian steroid receptor interactions which explain how the progressive change in steroid environments throughout folliculogenesis programs granulosa cells during the transition to ovulation.