The Emerging Role of Chromatin Remodeling Factors in Female Pubertal Development

Abstract

To attain sexual competence, all mammalian species go through puberty, a maturational period during which body growth and development of secondary sexual characteristics occur. Puberty begins when the diurnal pulsatile gonadotropin-releasing hormone (GnRH) release from the hypothalamus increases for a prolonged period of time, driving the adenohypophysis to increase the pulsatile release of luteinizing hormone with diurnal periodicity. Increased pubertal GnRH secretion does not appear to be driven by inherent changes in GnRH neuronal activity; rather, it is induced by changes in transsynaptic and glial inputs to GnRH neurons. We now know that these changes involve a reduction in inhibitory transsynaptic inputs combined with increased transsynaptic and glial excitatory inputs to the GnRH neuronal network. Although the pubertal process is known to have a strong genetic component, during the last several years, epigenetics has been implicated as a significant regulatory mechanism through which GnRH release is first repressed before puberty and is involved later on during the increase in GnRH secretion that brings about the pubertal process. According to this concept, a central target of epigenetic regulation is the transcriptional machinery of neurons implicated in stimulating GnRH release. Here, we will briefly review the hormonal changes associated with the advent of female puberty and the role that excitatory transsynaptic inputs have in this process. In addition, we will examine the 3 major groups of epigenetic modifying enzymes expressed in the neuroendocrine hypothalamus, which was recently shown to be involved in pubertal development and progression.

Keywords: Epigenetics; GnRH; Kiss1; Puberty.

Figure 1:. Hypothalamic regulation of pulsatile GnRH release.

The control of puberty is exerted by excitatory and inhibitory transsynaptic inputs to GnRH neurons. The current concept claims that the initiation of puberty implicates a shift from a mainly inhibitory to a stimulatory mode of control. This results in the diurnal activation of pulsatile GnRH release, leading to increased LH pulsatility, which is the first endocrine manifestation of puberty. Changes in pulsatile GnRH release are due to decreased inhibitory neurotransmission (GABA, Opioids, RFamide) and concomitant increased activation of stimulatory neuronal (Glutamate, Kisspeptins) and glial (TGFa, PGE2) networks that operate within the ARC nucleus of the hypothalamus. These neuronal and glial systems affect GnRH pulsatility by predominantly targeting GnRH nerve terminals reaching the median eminence. The preovulatory surge of gonadotropins is triggered by the positive feedback of estradiol on AVPV kisspeptin neuronal activation.

Figure 2:. Chromatin structure and the epigenetic code.

Heterochromatin is a tightly packed combination of DNA and histone octamers that is associated with less active gene transcription. Euchromatin is less condensed and associated with active gene transcription. Epigenetic writers (brown hexagons) modify the amino acid residues of histone tails, building the histone code at DNA regulatory regions. Epigenetic readers (blue semi-circles) bind to these epigenetic marks and help recruit transcription factors and other epigenetic modifiers. Epigenetic erasers (yellow circles) catalyze the removal of epigenetic marks. The balance of these enzymatic pathways, and thus the balance between hetero and euchromatin, is what renders a gene in active or silent state.

Figure 3:. Diagram depicting the changes in histone marks and epigenetic enzymes at the promoter region of the Kiss1 gene during the infantile to pubertal transition.

During the infantile period, when LH pulsatility is low, the expression of several epigenetic repressors (Eed, GATAD1 and SIRT1 is elevated in the ARC. The presence of these epigenetic repressors at the Kiss1 promoter/enhancer region produces a histone landscape associated with transcriptional repression (high levels of H3K27me3 and low levels of H3K4me3, H3K9/14ac and H4K16ac). As a result of this, Kiss1 expression remains low. As puberty progresses, the expression of these epigenetic repressors diminishes while the expression of members of the TrxG of epigenetic activators increases. Increased binding of MLL1 and MLL3 to the Kiss1 promoter and enhancer region respectively shifts the epigenetic landscape of the Kiss1 regulatory region into a more active state (low levels of H3K27me3 and high levels of H3K4me3, H3K9/14ac and H4K16ac). This results in increased recruitment of RNA Polymerase 2 and enhanced Kiss1 expression at puberty.