Neuroendocrine control of female puberty: Genetic and epigenetic regulation

Puberty is a major developmental milestone that occurs at a postnatal age widely different in different species. Although the factors responsible for this species-specific time frame remain unknown, it appears clear that the interaction of genetic factors and environmental cues plays an important role in defining the timing of puberty. From the neuroendocrine point of view, the initiation of puberty requires a sustained increase in pulsatile release of gonadotropin-releasing hormone (GnRH) from neurosecretory neurons of the hypothalamus. In turn, this increase is not dependent on primary alterations in the physiology of GnRH neurons, but instead it results from alterations in the output of neuronal and glial systems functionally connected to the GnRH neuronal network. Although single genes have been identified that are essential for puberty to occur, it now appears clear that activation of the pubertal process requires the contribution of many genes controlling diverse cellular functions in different cellular subsets. The polygenic nature of this controlling mechanism suggests that the genes involved are not only functionally connected, but are also subjected to an encompassing and dynamic level of control independent of changes in DNA sequence. This chapter discusses emerging evidence suggesting that the onset of puberty is controlled at the transcriptional level by interactive gene networks subjected to epigenetic regulation. We suggest that epigenetic information provides coordination and plasticity to these networks by using at least two regulatory mechanisms: changes in DNA methylation and changes in the landscape of histone posttranslational modifications associated with genomic regions controlling the activity of puberty-related genes. Finally, the concept is advanced that two essential components of puberty-controlling transcriptional gene networks are ‘activators’ that move the process along by setting in motion key developmental events, and ‘repressors’ that prevent the premature manifestation of these events.