Epigenetic regulation of puberty via Zinc finger protein-mediated transcriptional repression

Abstract

In primates, puberty is unleashed by increased GnRH release from the hypothalamus following an interval of juvenile quiescence. GWAS implicates Zinc finger (ZNF) genes in timing human puberty. Here we show that hypothalamic expression of several ZNFs decreased in agonadal male monkeys in association with the pubertal reactivation of gonadotropin secretion. Expression of two of these ZNFs, GATAD1 and ZNF573, also decreases in peripubertal female monkeys. However, only GATAD1 abundance increases when gonadotropin secretion is suppressed during late infancy. Targeted delivery of GATAD1 or ZNF573 to the rat hypothalamus delays puberty by impairing the transition of a transcriptional network from an immature repressive epigenetic configuration to one of activation. GATAD1 represses transcription of two key puberty-related genes, KISS1 and TAC3, directly, and reduces the activating histone mark H3K4me2 at each promoter via recruitment of histone demethylase KDM1A. We conclude that GATAD1 epitomizes a subset of ZNFs involved in epigenetic repression of primate puberty.

Global differential gene expression in the pituitary gland and the ovaries of pre- and postpubertal Brahman heifers

“…These five TF were all zinc fingers that were downregulated after puberty. This result confirmed previous studies noting the decrease of zinc finger gene expression after puberty in monkeys (Lomniczi et al, 2015).…”

“…Interactions between zinc finger genes and predicted target genes need validation beyond our coexpression results. Interactions between zinc finger genes and targets considered puberty-activating genes are of particular interest to further unveil the proposed mechanisms of puberty (Lomniczi et al, 2015). Before puberty, zinc finger genes are proposed to inhibit puberty-activating genes.…”

“…Furthermore, studies in male and female mice indicated that there was an increase of MKRN3/ZNF127 mRNA levels in prepubertal heifers, a reduction in levels immediately before puberty, and low levels after puberty (Abreu et al, 2013). Decreased expression of zinc finger genes including GATAD1 and ZNF573 in peripubertal female monkeys was reported (Lomniczi et al, 2015). In fact, GATAD1 was suggested to have a dual role in both contributing to GnRH release at the occurrence of puberty and silencing GnRH pulse generator at the infantile-early juvenile transition.…”

“…Four novel genes were predicted zinc finger targets in the subnetwork, 2 upregulated and 2 downregulated; these results are the first report of their potential function as puberty-related genes. Lomniczi et al (2015) reported zinc finger genes as a subnetwork controlling the onset of female puberty. In the studied Brahman heifers, zinc fingers were DEx and/or important TF in the hypothalamus (Fortes et al, 2016), the pituitary gland, and the ovaries (as reported herein).…”

Understanding the epigenetic basis of sex differences in depression

“…There is substantial evidence that there are epigenetic mechanisms underlying the onset of puberty in females—notably DNA methylation (Lomniczi et al 2013), histone modification (Lomniczi et al 2015) and non-coding RNAs (Sangiao-Alvarellos et al 2013). However, in these studies, sex differences were rarely investigated and the timing of puberty does not seem to significantly influenced by the peripubertal hormone rise but is instead a product of central changes in hypothalamus that drives peripheral pubertal changes, a hypothesis referred to as the “central drive hypothesis of puberty” (Herbison 2016).…”