Estrogen receptor β mediates the feedback loop between 17β-Estradiol and CYP19A1, which controls transcriptomic stability, inhibits granulosa cell apoptosis, induces oocyte maturation and influences sow fertility

17β-Estradiol (E2), secreted by granulosa cells (GCs), is essential for ovarian development and female fertility. However, its action mechanism and synthetic regulation remain elusive. Here, functional analysis showed that E2, highly synthesized in dominant follicles, effectively inhibited GC Apoptosis. RNA-seq revealed that the impact of E2 was at a transcriptome-wide scale, and 1326 estrogen responsive elements (EREs) were identified in the promoter of 72.8 % (653/897) of the differentially expressed genes. ChIP assays showed that Estrogen receptor β (ERβ) mediated the regulation of E2 on transcriptome in a transcription factor activity-dependent manner. Furthermore, a novel anti-apoptotic feedback regulatory loop, E2/ERβ/CYP19A1, was identified. Specifically, E2 activates ERβ, which induces CYP19A1 transcription by directly binding to its promoter. Notably, ESR2 c.949G > A, a missense SNV associated with sow reproductive traits, affects cumulus expansion and oocyte maturation, with A being the favourable allele. Mechanistically, it causes p.V317M substitution, which locates in the ligand binding domain of ERβ and influences its sensitivity to E2. Our findings highlight the critical role of ERβ in mediating the feedback regulation and anti-apoptotic function of E2 in GCs, and its feasibility as a candidate causal gene for sow fertility, providing valuable clues for steroid hormone regulation and female fertility improvement.

E2-CYP19A1 feedback loop; ERβ; GC apoptosis; Reproductive traits; Single nucleotide polymorphism.