Androgens regulate ovarian gene expression by balancing Ezh2-Jmjd3 mediated H3K27me3 dynamics

摘要: 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 the ovary. Using mouse models, this study provides three insights about androgen-induced gene regulation ovary and its impact on First, RNA-sequencing reveals number genes biological processes that were previously not known be directly regulated by Second, can also influence expression decreasing tri-methyl mark lysine 27 histone3 (H3K27me3), silencing epigenetic mark. ChIP-seq analyses highlight modulation H3K27me3 within bodies, promoters or distal enhancers much broader ovarian function than genomic effects androgens. Third, decrease is mediated through (a) inhibiting activity Enhancer Zeste Homologue 2 (EZH2), histone methyltransferase promotes tri-methylation K27 (b) inducing demethylase called Jumonji domain containing protein-3 (JMJD3/KDM6B), responsible for removing Androgens PI3K/Akt pathway, transcription-independent fashion, increase hypoxia-inducible factor 1 alpha (HIF1α) protein levels, which turn induce JMJD3 expression. Furthermore, proof concept studies involving vivo knockdown Ar (granulosa) cell-specific knockout model show regulate key H3K27me3.