Estrogen Receptor Alpha and Beta Chromatin Interactions Govern Ovarian Folliculogenesis but Dissipate During Ovulation

Estrogen signalling plays an important role in normal ovarian functions, including follicle development, ovulation and ovarian cell identity maintenance. Estrogen acts through the estrogen receptors alpha (ERα) and beta (ERβ), both of which are involved in ovarian gene regulation. However, the molecular mechanisms that lead to shared and unique receptor actions in the ovary remain poorly understood. Additionally, co-regulators that contribute to estrogen receptor actions in the ovary have remained unexplored. Here, we distinguished the roles of ERα and ERβ at different ovarian stages through characterising the chromatin binding profile of each receptor in granulosa cells during pre- or peri-ovulation. We found that ERα/β genomic action was prominent during follicle development prior to ovulation. Loss of ERα/β binding after LH-stimulus was associated with the downregulation of folliculogenesis genes, while ERα/β binding contributed little to the activation of genes that are required for ovulation. ERα and ERβ showed highly similar chromatin binding patterns in granulosa cells. Through motif enrichment analysis and integration of other ovarian transcription factor cistromes, we identified potential interactors of ERα and ERβ, including a very strong overlap in chromatin binding with androgen receptor (AR) in pre-ovulatory follicles. These findings demonstrate ERα and ERβ to have highly conserved chromatin interaction functions including interaction with AR to mediate gene expression during folliculogenesis.