The Epigenetic Regulation of Puberty

描述（由申请人提供）：青春期的开始是一个鲜为人知的发育转变，其标志是下丘脑GnRH神经内分泌活性增加。我们的长期目标是确定与青春期上游调控和下丘脑GnRH神经元活动所需基因转录变化启动相关的关键因素。通过小鼠模型，我们证实了在青春期成熟过程中，下丘脑对kisspeptin和neurokinin B神经肽的激素依赖性和非依赖性激活，这证实了弓形核（ARC）是青春期激活的关键中心。我们假设表观遗传因素对这些重要的神经内分泌生殖基因的表达有重要影响，从而改变青春期开始的时间。我们展示了赖氨酸特异性去甲基酶1 （LSD1/KDM1）的作用证据，这是一种参与染色质重塑的组蛋白修饰酶，已被证明在发育和细胞转化模型中作为转录激活因子和抑制因子。初步数据显示，在青春期时，ARC中的LSD1表达增加。此外，我们对LSD1小鼠模型的研究表明，LSD1单倍不足会导致青春期标志物的提前和发情周期的破坏，这表明LSD1在生殖中枢激活中起调节作用。因此，我们进一步假设LSD1是ARC核中kisspeptin和neurokinin B的上游转录调节剂，并通过青春期过渡的表观基因组门控机制成为青春期开始的候选调节剂。这项提议的目的是确定LSD1在青春期开始中的确切作用，以及LSD1对生殖的表观遗传调节的贡献。我们建议在下丘脑区域确定LSD1对青春期至关重要的变化，并在体内功能测试LSD1对标志着青春期发育开始的神经内分泌事件的贡献。具体而言，我们建议：(1)研究LSD1在青春期成熟期ARC中的表达、定位、活性和基因靶点；(2)确定ARC神经元发育和成熟的变化对LSD1小鼠阴道开放加速和首次发情年龄的贡献；(3)确定调节ARC中LSD1的表达和活性对体内青春期开始时间和生殖功能的影响。本研究的成功完成将有助于阐明LSD1和表观遗传修饰在青春期发育中枢激活中的作用。这些研究可能会导致确定新的目标，以控制青春期开始的时间和治疗青春期和生殖障碍。

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.