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

Nat Commun. 2015 Dec 16:6:10195. doi: 10.1038/ncomms10195.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • Epigenesis, Genetic*
  • Female
  • Fluorescent Antibody Technique
  • Follicle Stimulating Hormone / metabolism
  • GATA Transcription Factors / genetics*
  • GATA Transcription Factors / metabolism
  • Gene Expression Regulation, Developmental*
  • Gonadotropin-Releasing Hormone / metabolism
  • Gonadotropins / metabolism
  • Histone Demethylases / metabolism
  • Hypothalamus / metabolism*
  • In Situ Hybridization, Fluorescence
  • Kisspeptins / genetics
  • Kisspeptins / metabolism
  • Luteinizing Hormone / metabolism
  • Macaca mulatta
  • Male
  • Neurokinin B / genetics
  • Neurokinin B / metabolism
  • Puberty / genetics*
  • RNA, Messenger / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Zinc Fingers / genetics

Substances

  • GATA Transcription Factors
  • GATA zinc finger domain containing 1, rat
  • Gonadotropins
  • Kisspeptins
  • RNA, Messenger
  • Gonadotropin-Releasing Hormone
  • Neurokinin B
  • Luteinizing Hormone
  • Follicle Stimulating Hormone
  • Histone Demethylases

Associated data

  • GEO/GSE64347
  • GEO/GSE64396