ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Nat Commun. 2018 Jan 4;9(1):57

The hypothalamic-pituitary-gonadal axis controls the onset of puberty and the acquisition of the reproductive function. A subset of neurons in the anterior hypothalamus secretes gonadotropin-releasing hormone (GnRH) which, through its pattern of release controls all aspects of reproduction throughout life. The secretory activity of GnRH neurons depends on trans-synaptic and glial inputs mediated by neurotransmitters and cell-cell signaling molecules¹. Primary trans-synaptic mechanisms underlying pulsatile GnRH release involve a specialized subset of neurons located in the arcuate nucleus of the medial basal hypothalamus. They have been termed KNDy neurons, because they produce kisspeptin, neurokinin B and dynorphin. The authors had previously shown that the secretory activity of KNDy neurons is kept in check during female prepubertal development by an epigenetic mechanism of transcriptional repression, exerted by the Polycomb group (PcG) of transcriptional silencers^1-3. PcG proteins repress the Kiss1 gene to prevent the premature initiation of the pubertal process, and this effect takes place against a backdrop of repressive chromatin, that is, rich in histone modifications associated with gene repression and depleted of histone modifications associated with gene activation.

Here, the authors now show that, on the one hand, MLL1 recruited to the promoter region of Kiss1 and Tac3 establishes a permissive chromatin configuration required for transcriptional activation. On the other hand, MLL3 acts at an ARC-specific Kiss1 enhancer site to implement a chromatin structure that facilitates enhancer activation. As these changes take place, eviction of key member of the PcG complex from the Kiss1 enhancer and from the Kiss1 (encoding Kisspeptin) and Tac3 (encoding Neurokinin B) promoters results in loss of PcG-mediated repression at each of these genomic sites. Thus, the authors identified the presence of both repressive and stimulatory epigenetic pathways regulating Kiss1 and Tac3 expression in KNDy neurons. This suggests that a switch from epigenetic repression to activation within these neurons underlies the developmental process by which GnRH release increases by late juvenile development to bring about the pubertal process.

1. Lomniczi A, Wright H, Ojeda SR. Epigenetic regulation of female puberty. Front Neuroendocrinol. 2015 Jan;36:90-107.

2. Lomniczi A, Wright H, Castellano JM, Matagne V, Toro CA, Ramaswamy S, Plant TM, Ojeda SR. Epigenetic regulation of puberty via Zinc finger protein-mediated transcriptional repression. Nat Commun. 2015 Dec 16;6:10195

3. Lomniczi A, Loche A, Castellano JM, Ronnekleiv OK, Bosch M, Kaidar G, Knoll JG, Wright H, Pfeifer GP, Ojeda SR. Epigenetic control of female puberty. Nat Neurosci. 2013 Mar;16(3):281-9.