Jumonji Domain–containing Protein-3 (JMJD3/Kdm6b) Is Critical for Normal Ovarian Function and Female Fertility

In females, reproductive success is dependent on the expression of a number of genes regulated at different levels, one of which is through epigenetic modulation. How a specific epigenetic modification regulates gene expression and their downstream effect on ovarian function are important for understanding the female reproductive process. The trimethylation of histone3 at lysine27 (H3K27me3) is associated with gene repression. JMJD3 (or KDM6b), a jumonji domain-containing histone demethylase specifically catalyzes the demethylation of H3K27me3, that positively influences gene expression. This study reports that the expression of JMJD3 specifically in the ovarian granulosa cells (GCs) is critical for maintaining normal female fertility. Conditional deletion of Jmjd3 in the GCs results in a decreased number of total healthy follicles, disrupted estrous cycle, and increased follicular atresia culminating in subfertility and premature ovarian failure. At the molecular level, the depletion of Jmjd3 and RNA-seq analysis reveal that JMJD3 is essential for mitochondrial function. JMJD3-mediated reduction of H3K27me3 induces the expression of Lif (Leukemia inhibitory factor) and Ctnnb1 (β-catenin), that in turn regulate the expression of key mitochondrial genes critical for the electron transport chain. Moreover, mitochondrial DNA content is also significantly decreased in Jmjd3 null GCs. Additionally, we have uncovered that the expression of Jmjd3 in GCs decreases with age, both in mice and in humans. Thus, in summary, our studies highlight the critical role of JMJD3 in nuclear-mitochondrial genome coordination that is essential for maintaining normal ovarian function and female fertility and underscore a potential role of JMJD3 in female reproductive aging.