br A selective inhibitor of mammalian histone deacetylase tr

A selective inhibitor of mammalian histone deacetylase, trichostatin A, reduces GnRH mRNA expression Epigenetic mechanisms controlling GnRH expression have been reported, and these mechanisms may be involved in the development and maturation of GnRH neurons in the brain (Gan et al., 2012, Kurian et al., 2010). These reports suggested that GnRH expression may be modulated by changes in chromatin structure and modification of histone. Novaira et al. (2012) clearly demonstrated the ability of kisspeptin to modify chromatin conformation and increase the binding of transcription factors to GnRH promoters. In our studies using GT1-7 cells, we have found that the modification of chromatin structure changes the GnRH mRNA expression in these cells. In these experiments, we applied trichostatin A (TSA), a selective inhibitor of histone deacetylase. TSA is an experimental reagent that modifies gene expression by opening the chromatin structure through hyperacetylation of histones (Tsuji et al., 1976). These changes in chromatin structure allow transcription factors to bind DNA and modify gene expression. Modification of DNA structure by TSA significantly reduced GnRH mRNA expression in GT1-7 cells. In addition, these experiments revealed that expression of the gene encoding retinaldehyde dehydrogenase (RALDH), which catalyzes the oxidation of retinol to the lipid-soluble retinoic Rosiglitazone (RA) (Duester, 2000), was concomitantly increased by TSA stimulation (Kanasaki et al., 2015). Considering the observations that RA itself similarly reduces GnRH expression in GT1-7 cells (Kanasaki et al., 2015), epigenetic mechanisms involving chromatin modification might have some inhibitory effect on GnRH synthesis through RALDH and RA. However, at present, the detailed mechanisms underlying the effect of TSA or RALDH/RA on GnRH synthesis remain unknown.
Conclusion After the discovery of GnRH in 1971, many experiments have been performed to evaluate its actions and the mechanisms of its regulation. The relatively recent discovery of kisspeptin and its receptor facilitated a greater understanding of the HPG axis; however, neuronal control of GnRH is still largely unknown. Studies concerning the regulation of GnRH neurons are relatively scarce because of the inherent difficulty in isolating single populations of GnRH neurons from the hypothalamus. In this review, we summarized our understanding of GnRH regulation using a GnRH-producing cell model, GT1-7 (Fig. 1). GT1-7 cells express Kiss1R and respond to kisspeptin, but our line of GT1-7 cells does not exhibit increases in GnRH gene expression upon kisspeptin stimulation. Instead, kisspeptin increased GnRH receptor expression. Considering the observation that hypothalamic PACAP also modulates the expression levels of the GnRH receptor, the functions of GnRH-producing cells might be influenced by the density of receptors. In addition, we have found that the δ-GABAA receptor agonist DS1, as well as the histone deacetylase inhibitor TSA, reduces the expression of GnRH. RA also has an inhibitory effect of GnRH synthesis. The regulatory mechanisms of GnRH synthesis and secretion in GnRH-producing neurons remain largely unknown. Further studies would be helpful to determine ways to more precisely manipulate the HPG axis to develop more effective therapeutic agents for treating reproductive hormone-related disorders.
Declaration of interest
Funding This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (Grant No. 20791144).
Introduction Reproductive performance in different sheep production systems is one of the main components of production units (meat, wool, milk) [1]. In sheep, one of the major factors affecting fertility is embryonic mortality during the first 3 weeks of pregnancy [1]. The main causes of embryonic mortality are deficiency of luteal function, embryonic-uterine asynchrony and insufficient embryo development, which are manifested by reduced embryo signaling for the pregnancy establishment and decreased luteotrophic effect [[2], [3], [4]]. Inadequate luteal function is a common cause of embryonic losses in sheep [5]. Since the 80's, different therapeutic strategies have been used to improve luteal function, reduce embryonic mortality and improve reproductive performance. Luteotrophic hormones such as gonadotrophin releasing hormone (GnRH) or human chorionic gonadotrophin (hCG) were used for this purpose during early-luteal phase [[6], [7], [8], [9]] or late-luteal phase [[10], [11], [12], [13]]. These hormones administered in the luteal phase act indirectly or directly on the ovary, generate the formation of an accessory corpus luteum (acc-CL) and increase serum progesterone (P4) concentration [8,[14], [15], [16]]. Fernandez et al. [17] have shown that the administration of hCG on Day 4 after fixed time artificial insemination (FTAI) in ewes generated an acc-CL and increased serum P4 concentration. However, the administration of GnRH generated an acc- CL, but did not increase the concentration of serum P4 [17].