The Epigenetic Regulation of Puberty

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DESCRIPTION (provided by applicant): The initiation of puberty is a poorly understood developmental transition marked by increased hypothalamic GnRH neuroendocrine activity. Our long-term goal is to identify critical factors associated with the upstream regulation of puberty and the initiation of the transcriptional changes in genes required for GnRH neuronal activity within the hypothalamus. Using a mouse model, we have demonstrated hormone-dependent and - independent hypothalamic activation of the neuropeptides kisspeptin and neurokinin B across pubertal maturation that confirm the arcuate nucleus (ARC) as a critical center for pubertal activation. We hypothesize that epigenetic factors have an important influence on the expression of these essential neuroendocrine reproductive genes to modify the timing of the onset of puberty. We show evidence of a role for lysine-specific demethylase 1 (LSD1/KDM1), a histone-modifying enzyme involved in chromatin remodeling that has been shown to act as a transcriptional activator and repressor in models of development and cellular transformation. Preliminary data show an increase in LSD1 expression in the ARC at the time of puberty. Furthermore, our studies of an LSD1 mouse model show that LSD1 haploinsufficiency results in the advancement of markers of puberty and the disruption of estrous cyclicity, indicating a regulatory role for LSD1 in the central activation of reproduction. We therefore further hypothesize that LSD1 is an upstream transcriptional regulator of kisspeptin and neurokinin B in the ARC nucleus and is a candidate regulator of pubertal onset through an epigenomic gating mechanism at the pubertal transition. The goal of this proposal is to determine the precise role of LSD1 in the onset of puberty and the contribution of epigenetic regulation by LSD1 to reproduction. We propose to identify changes in LSD1 within hypothalamic areas critical for puberty and to functionally test the contributions of LSD1 to the neuroendocrine events that mark the initiation of pubertal development in vivo. Specifically, we propose to: (1) Characterize LSD1 expression, localization, activity, and gene targets in the ARC across pubertal maturation; (2) Determine the contributions of changes in ARC neuronal development and maturation to accelerated vaginal opening and age at first estrus in LSD1 mice; and (3) Determine the effects of modifying LSD1 expression and activity in the ARC on the timing of pubertal onset and reproductive function in vivo. The successful completion of the proposed studies will help to elucidate the contribution of LSD1 and epigenetic modifications to the central activation of pubertal development. These studies may lead to the identification of novel targets for the control of the timing of pubertal onset and for treatment of disorders of puberty and reproduction.) PUBLIC HEALTH RELEVANCE: The mechanism of pubertal onset has perplexed the understanding of human development and is considered to be among the great remaining scientific questions. We hypothesize that epigenetic factors, which are involved in changing DNA structure, have an important influence on the timing of the onset of puberty. We show evidence of a role for lysine-specific demethylase 1 (LSD1/KDM1), an epigenetic enzyme that can regulate gene activation and repression. Preliminary data demonstrate changes in LSD1 expression in the hypothalamus, an area important for pubertal development and reproductive function. In addition, pubertal onset occurs at younger ages and normal reproductive function is disrupted in mice with reduced levels of LSD1. The overall goal of this project is to determine the precise role of LSD1 in the onset of puberty and the contribution of epigenetic regulation by LSD1 to reproduction. We propose to identify changes in LSD1 within hypothalamic areas critical for puberty and to functionally test the contributions of LSD1 to the neuroendocrine events that mark the initiation of pubertal development in vivo.