Androgens Regulate Ovarian Gene Expression By Balancing Ezh2-Jmjd3 Mediated H3k27me3 Dynamics

Author summaryAndrogens are traditionally viewed as the male hormone. Interestingly, in the last couple of years, androgens have emerged as a key regulator of fertility and health in women. High androgens are associated with polycystic ovary syndrome (PCOS) and is detrimental to women's health. Conversely, androgen supplementation is now being used in clinical practice for a subgroup of women suffering from infertility as direct androgen actions are deemed essential for female fertility. However, in the ovary, which genes are regulated by androgens and how are poorly understood which is a limitation towards developing therapeutic or diagnostic strategies. We have discovered many important ovarian genes that were previously not known to be directly regulated by androgens. Additionally, we find that androgens influence the expression of a large number of ovarian genes critical for female fertility through epigenetic changes. Epigenetics govern whether a gene is "on" or "off" thereby affecting gene activity and expression. Here, we provide a mechanistic insight into how androgens decrease an epigenetic mark associated with gene repression. Our findings provide a comprehensive understanding of the overall impact of androgens on ovarian gene expression and physiology that can potentially improve female fertility and pathophysiological conditions like PCOS.Conventionally viewed as male hormone, androgens play a critical role in female fertility. Although androgen receptors (AR) are transcription factors, to date very few direct transcriptional targets of ARs have been identified in the ovary. Using mouse models, this study provides three critical insights about androgen-induced gene regulation in the ovary and its impact on female fertility. First, RNA-sequencing reveals a number of genes and biological processes that were previously not known to be directly regulated by androgens in the ovary. Second, androgens can also influence gene expression by decreasing the tri-methyl mark on lysine 27 of histone3 (H3K27me3), a gene silencing epigenetic mark. ChIP-seq analyses highlight that androgen-induced modulation of H3K27me3 mark within gene bodies, promoters or distal enhancers have a much broader impact on ovarian function than the direct genomic effects of androgens. Third, androgen-induced decrease of H3K27me3 is mediated through (a) inhibiting the expression and activity of Enhancer of Zeste Homologue 2 (EZH2), a histone methyltransferase that promotes tri-methylation of K27 and (b) by inducing the expression of a histone demethylase called Jumonji domain containing protein-3 (JMJD3/KDM6B), responsible for removing the H3K27me3 mark. Androgens through the PI3K/Akt pathway, in a transcription-independent fashion, increase hypoxia-inducible factor 1 alpha (HIF1 alpha) protein levels, which in turn induce JMJD3 expression. Furthermore, proof of concept studies involving in vivo knockdown of Ar in the ovary and ovarian (granulosa) cell-specific Ar knockout mouse model show that ARs regulate the expression of key ovarian genes through modulation of H3K27me3.