Endocrine Abstracts

A prevailing concept regarding the mechanism controlling the timing of puberty proposes that GnRH release from the hypothalamus increases at puberty due to a loss of transsynaptic inhibition, accompanied by an increase in neuronal/glial excitatory inputs to GnRH neurons. Without negating the importance of this intercellular communication process, recent evidence suggests that a critical inhibitory/excitatory Yin-Yang mechanism regulating the advent of puberty is epigenetic in nature and affects the transcriptional activity of neurons involved in stimulating GnRH release (such as kisspeptin neurons). The repressive arm of this mechanism is provided by the Polycomb group (PcG) of transcriptional silencers, which prevents the premature initiation of female puberty by silencing the Kiss1 gene in kisspeptin neurons of the arcuate nucleus (ARC) of the hypothalamus. At the end of juvenile development PcG proteins are evicted from the Kiss1 promoter and the abundance of the PcG-catalyzed, ‘repressive’, histone modification H3K27me3 is reduced. The antagonistic counterpart of PcG-mediated gene silencing is provided by the Trithorax (TrxG) group of transcriptional activators. Like the PcG complex, TrxG genes are expressed in kisspeptin neurons of the ARC. Key TrxG proteins required for the synthesis of ‘activating’ histone marks (histone 3 di- and trimethylated at lysine 4) are recruited to the Kiss1 promoter at the initiation of puberty and this correlates well with an increased abundance of the activating histone marks H3K4me3 and histone 3 acetylated at lysine 9 and 4 (H3K9, 14 ac) at the promoter. Both the PcG and the TrxG systems are, in turn) regulated by upstream repressors. Whereas PcG gene expression is inhibited by members of the POK (for POZ and Krüppel) family of transcriptional regulators, TrxG action is attenuated by zinc finger (ZNF) proteins that facilitate the demethylation of H3K4me2 via recruitment of a specific lysine demethylase (Kdm1a/LSD1) to the KISS1 and TAC3 promoters. The presence of this tight system of epigenetic regulation in KISS1/TAC3 expressing neurons of the ARC suggests that a switch from epigenetic repression to activation within these neurons underlies the developmental process by which GnRH release is first kept in check before puberty, and then increases by late juvenile development to bring about the pubertal process. (NSF grant 1121691)

Disclosure: National Science Foundation (USA) Grant IOS1121691.