Androgen-induced epigenetic modulations in the ovary

Abstract

In recent years, androgens have emerged as critical regulators of female reproduction and women's health in general. While high levels of androgens in women are associated with polycystic ovary syndrome (PCOS), recent evidence suggests that a certain amount of direct androgen action through androgen receptor is also essential for normal ovarian function. Moreover, prenatal androgen exposure has been reported to cause developmental reprogramming of the fetus that manifests into adult pathologies, supporting the Developmental Origins of Health and Disease (DOHaD) hypothesis. Therefore, it has become imperative to understand the underlying mechanism of androgen actions and its downstream effects under normal and pathophysiological conditions. Over the years, there has been a lot of studies on androgen receptor function as a transcriptional regulator in the nucleus as well as androgen-induced rapid extra-nuclear signaling. Conversely, new evidence suggests that androgen actions may also be mediated through epigenetic modulation involving both the nuclear and extra-nuclear androgen signaling. This review focuses on androgen-induced epigenetic modifications in female reproduction, specifically in the ovary, and discusses emerging concepts, latest perceptions, and highlight the areas that need further investigation.

Keywords: DNA methylation; androgens; developmental programming; epigenetics; female reproduction; histone modification.

Figure 1.

(A) Androgen-induced histone modifications occur in the distal enhancer and/or promoter regions of genes that in turn regulate gene expression. (B) Mechanism of Androgen-induced histone modifications: Androgens through activation PI3K/Akt pathway and induction of miR-101 expression inhibit the enzymatic activity and expression of EZH2, a histone methyl transferase responsible for trimethylation of lysine 27 on histone 3 (H3K27me3), a gene repressive mark. (C) Androgen receptors also recruit LSD1, a lysine-specific histone demethylase 1A that demethylates mono- or di-methyl lysine 4 and 9 on histone 3 (H3K4/9me1/2).

Figure 2.

Androgen-induced regulation of DNA methylation: It is being proposed that androgens may indirectly regulate gene expression through regulating the expression and/or enzymatic activity of DNA methyltransferases and/or DNA demethylases that in turn mediates the methylation pattern of CpG islands. The changes in the methylation pattern are tissue- / cell-type specific and causes developmental reprogramming.