The role of the hypothalamus and pituitary epigenomes in central activation of the reproductive axis at puberty

Puberty is programmed through a multifactorial gene network which works to activate the pulsatile secretion of the gonadotropin releasing hormone (GnRH), and subsequently elevate circulating levels of the pituitary gonadotropins that stimulate gonadal activity. Although this developmental transition normally occurs at a limited age-range in individuals of the same genetic background and environment, pubertal onset can occur prematurely or be delayed following changes in ambient conditions, or due to genetic variations or mutations, many of which have remained elusive due to their location in distal regulatory elements. Growing evidence is pointing to a pivotal role for the epigenome in regulating key genes in the reproductive hypothalamus and pituitary at this time, which might mediate some of the plasticity of pubertal timing. This review will address epigenetic mechanisms which have been demonstrated in the KNDy neurons that increase the output of pulsatile GnRH, and those involved in activation of the GnRH gene and its receptor, and describes how GnRH utilizes epigenetic mechanisms to stimulate transcription of the pituitary gonadotropin genes in the context of the chromatin landscape.