Emerging Roles of Epigenetics in the Control of Reproductive Function: Focus on Central Neuroendocrine Mechanisms

Abstract

Reproduction is an essential function for perpetuation of the species. As such, it is controlled by sophisticated regulatory mechanisms that allow a perfect match between environmental conditions and internal cues to ensure adequate pubertal maturation and achievement of reproductive capacity. Besides classical genetic regulatory events, mounting evidence has documented that different epigenetic mechanisms operate at different levels of the reproductive axis to finely tune the development and function of this complex neuroendocrine system along the lifespan. In this mini-review, we summarize recent evidence on the role of epigenetics in the control of reproduction, with special focus on the modulation of the central components of this axis. Particular attention will be paid to the epigenetic control of puberty and Kiss1 neurons because major developments have taken place in this domain recently. In addition, the putative role of central epigenetic mechanisms in mediating the influence of nutritional and environmental cues on reproductive function will be discussed.

Keywords: GnRH; Kiss1; environmental cues; epigenetics; kisspeptins; nutrition; puberty; reproduction.

Figure 1.

Basic epigenetic mechanisms for the control of gene expression. A schematic of the major epigenetic phenomena affecting gene expression is presented. Epigenetic mechanisms operate “upon” the DNA sequence to modulate gene expression, either by methylation of CpG islands or by histone posttranslational modifications. Repressive mechanisms are indicated on the left, whereas activator events are depicted on the right. Suppressive mechanisms involve also the action of miRNAs, which can promote mRNA degradation or block translation. For further details, see the text.

Figure 2.

Epigenetic mechanisms for the control of relevant genes in reproduction. A schematic is shown for the major mechanisms described to date in the epigenetic control of key reproductive genes at different developmental periods. Data from rodent studies showed that Kiss1 expression during pubertal transition is determined by the counterbalance between PcG and TrxG regulatory components, acting at Kiss1 promoter, in ARC Kiss1 neurons. During the juvenile period, the predominance of PcG elements at its promoter keeps Kiss1 repressed. During the pubertal transition, the eviction of EED and CBX7 (PcG members), together with the abundance of TrxG elements at Kiss1 promoter, induces a reorganization of the chromatin landscape. As a result, chromatin changes to a permissive configuration due to the elevation of the activator histone marks, H3K9/14ac and H3K4me3, and the decreased of the inhibitory mark, H3k27me3. Consequently, RNA pPolymerase II (POL-II) is recruited, Kiss1 expression is activated and puberty is attained. In adulthood, the preovulatory surge of gonadotropins is mediated by an estrogen-dependent activation of AVPV Kiss1 neurons in the female. Thus, the elevation of the circulating levels of estradiol (E2) during the morning of proestrus stimulates acetyl-H3 content (H3K9/14) at Kiss1 promoter, leading to AVPV-specific Kiss1 expression upregulation. Finally, it has been recently documented the implication of ZNF proteins in the control of KISS1 and TAC3 expression. At the infantile period, GATAD1, a ZNG finger protein, recruits a histone demethylase, KDM1A, to KISS1 and TAC3 promoters, leading to demethylation of the activator mark H3K4me2 and therefore blockade of KISS1 and TAC3 expression. During pubertal transition, eviction of the repressor complex (GATAD1/ KDM1A) permits enhanced KISS1 and TAC3 expression and pubertal activation002E.