The Epigenetic Regulation of Puberty

描述（由申请方提供）：青春期的开始是一种尚不清楚的发育转变，其特征是下丘脑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相关的关键因素，以及下丘脑内GnRH神经元活性所需基因转录变化的启动。使用小鼠模型，我们已经证明了神经肽kisspeptin和神经激肽B跨青春期成熟，确认弓状核（ARC）作为青春期激活的关键中心的依赖性和非依赖性下丘脑激活。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，以修改青春期开始的时间。我们显示了赖氨酸特异性脱甲基酶1（LSD 1/KDM 1）的作用的证据，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充当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LSD 1表达增加。此外，我们对LSD 1小鼠模型的研究表明，LSD 1单倍不足导致青春期标志物的进展和发情周期的破坏，表明LSD 1在生殖中枢激活中的调节作用。因此，我们进一步假设LSD 1是ARC核中kisspeptin和神经激肽B的上游转录调节因子，并且是通过青春期过渡期的表观基因组门控机制的青春期开始的候选调节因子。该提案的目标是确定LSD 1在青春期开始中的确切作用以及LSD 1对生殖的表观遗传调节的贡献。我们建议确定下丘脑内的青春期关键领域的LSD 1的变化，并在功能上测试LSD 1的神经内分泌事件，标志着青春期发育的启动在体内的贡献。具体而言，我们建议：（1）表征青春期成熟过程中ARC中LSD 1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LSD 1小鼠首次发情时阴道张开和年龄加速的贡献;（3）确定改变ARC中LSD 1的表达和活性对青春期开始时间和体内生殖功能的影响。这些研究的成功完成将有助于阐明LSD 1和表观遗传修饰对青春期发育中枢激活的贡献。这些研究可能会导致识别新的目标，用于控制青春期开始的时间和治疗青春期和生殖障碍。 公共卫生相关性：青春期开始的机制一直困扰着人类对发育的理解，并被认为是重大的科学问题之一。我们假设，表观遗传因素，这是参与改变DNA结构，有一个重要的影响青春期开始的时间。我们显示了赖氨酸特异性脱甲基酶1（LSD 1/KDM 1）的作用的证据，LSD 1/KDM 1是一种可以调节基因激活和抑制的表观遗传酶。初步数据表明，下丘脑中LSD 1表达的变化，这是青春期发育和生殖功能的重要区域。此外，青春期的开始发生在较年轻的年龄和正常的生殖功能被破坏的小鼠与LSD 1水平降低。该项目的总体目标是确定LSD 1在青春期开始中的确切作用以及LSD 1对生殖的表观遗传调节的贡献。我们建议确定下丘脑内的青春期关键领域的LSD 1的变化，并在功能上测试LSD 1的神经内分泌事件，标志着青春期发育的启动在体内的贡献。

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.