Epigenetic and transcriptional regulation of ovarian development altered in Erβ KO ovaries

Abstract We analyzed the transcriptome of wildtype and estrogen receptor β knockout (Erβ KO ) rat ovaries during the early postnatal period and detected remarkable changes in epigenetic regulators and transcription factors. Compared to postnatal day (PD) 4.5 wildtype ovaries, 17 differentially expressed epigenetic regulators (DEERs), and 23 differentially expressed transcription factors (DETFs) were detected in PD6.5 wildtype ovaries. Subsequently, compared to PD 6.5 wildtype ovaries, 24 DEERs and 68 DETFs were detected in PD8.5 ovaries. Changes in DEERs and DEFTs resulted in 581 differentially expressed downstream genes (DEDGs) in PD6.5 and 920 DEDGs in wildtype PD8.5 ovaries. The DEERs, DETFs, and DEDGs in wildtype ovaries represented primordial follicle activation (PFA) and development of the first-wave follicles because the second-wave follicles remain dormant during this period. However, the changes in DEERs, DETFs, and DEDGs during this postnatal period were markedly different in Erβ KO rat ovaries, which suffered from increased PFA in both waves. Compared to 17 DEERs and 23 DETFs in wildtype, 46 DEERs and 55 DETFs were identified in PD 6.5 Erβ KO ovaries. The differences were more remarkable in PD 8.5 Erβ KO ovaries; compared to 24 DEERS and 68 DETFs in wildtype, only 8 DEERs and 10 DETFs were detected in Erβ KO ovaries. Such dysregulation resulted in altered DEDGs in PD 6.5 (581 vs. 744) and in PD8.5 (920 vs. 191) Erβ KO ovaries. These findings also suggest that the number of DEDGs depends directly on the numbers of DEERS and DETFs. In addition to the quantitative differences in DEERs and DETFs between the wildtype and Erβ KO ovaries, we detected distinct differences in the identities of the regulators. Our observations indicate that loss of ERβ dysregulates the epigenetic regulators and transcription factors in Erβ KO ovaries, which disrupts the downstream genes in ovarian follicles and increases follicle activation.