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节和启动下丘脑内GnRH神经元活动所需基因转录变化相关的关键因素。使用小鼠模型，我们已经证明了下丘脑在青春期成熟期间对神经肽Kispeptin和神经激肽B的激活依赖于激素和不依赖于激素，这证实了弓状核(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必需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。我们证明了赖氨酸特异性去甲基酶1(LSD1/KDM1)的作用，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扮演转录激活和抑制因子的角色。初步数据显示，在青春期时，LSD1在ARC中的表达增加。此外，我们对LSD1小鼠模型的研究表明，LSD1单倍体不足导致青春期标志物的提前和动情周期的中断，表明LSD1在生殖的中枢激活中起着调节作用。因此，我们进一步假设LSD1是ARC核中Kispeptin和Neurkinin B的上游转录调节因子，并且是青春期开始时通过表观基因组门控机制的候选调节因子。这项建议的目的是确定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。我们建议确定LSD1在下丘脑对青春期至关重要的区域的变化，并从功能上测试LSD1在体内标志着青春期发育开始的神经内分泌事件中的作用。具体地说，我们建议：(1)表征青春期成熟过程中ARC中LSD1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发情初期年龄的影响；以及(3)在体内确定改变ARC中LSD1的表达和活性对青春期开始时间和生殖功能的影响。拟议研究的成功完成将有助于阐明LSD1和表观遗传修饰对青春期发育的中心激活的贡献。这些研究可能导致确定新的目标，以控制青春期开始的时间和治疗青春期和生殖障碍。 与公共卫生相关：青春期发作的机制一直困扰着对人类发展的理解，被认为是遗留下来的重大科学问题之一。我们假设，参与改变DNA结构的表观遗传因素对青春期开始的时间有重要影响。我们证明了赖氨酸特异性脱甲基酶1(LSD1/KDM1)的作用，这是一种表观遗传酶，可以调节基因的激活和抑制。初步数据显示，LSD1在下丘脑的表达发生了变化，下丘脑是青春期发育和生殖功能的重要区域。此外，LSD1水平降低的小鼠青春期发作更早，正常生殖功能受到干扰。这个项目的总体目标是确定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控的贡献。我们建议确定LSD1在下丘脑对青春期至关重要的区域的变化，并从功能上测试LSD1在体内标志着青春期发育开始的神经内分泌事件中的作用。

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.