Ovarian reserve formation and maintenance

摘要 这项研究的目标是了解居住在原始卵泡中的卵母细胞的表观遗传状态 有助于维持女性的卵巢储备。卵巢储备定义了女性的生殖能力 寿命，在人类中跨越数十年，这是由于居住在 原始毛囊。卵母细胞的质量和数量是卵巢功能的关键决定因素， 原始卵泡衰竭会触发更年期。然而，我们对卵巢储备是如何 由于无法进行分子分析，目前生成和维护的数据有限。在我们的 在未发表的研究中，我们开发了一种协议来分离未生长的卵母细胞池，从而使分子 分析。我们发现，多梳抑制复合体1在 直接抑制减数分裂前期I基因表达程序的围产期小鼠卵母细胞，从而 允许过渡到Dictyate逮捕。基于这些发现，我们提出染色质状态是 在围产期卵子发生期间建立的，使卵巢储备形成，然后在成人中维持 和老化的卵巢。在目标1中，我们将对初始的非 来自幼年卵巢的不断增长的卵母细胞和成年后维持的卵巢储备。目标1将建立一个 卵巢储备的表观基因组数据来源。在AIM2中，我们设计了一种基于候选的方法来定义 染色质在卵巢储备中的调节机制。我们将确定CHD4的功能， 染色质改进剂，维持卵巢储备。目标2将为调查 以染色质为基础的卵巢储备维持机制。拟议中的研究将显著地 通过提供卵巢储备的表观基因组是如何建立的和如何建立的分子洞察来推进该领域 维护好了。

ABSTRACT The goal of this study is to understand how epigenetic states in oocytes that reside in primordial follicles contribute to maintenance of the ovarian reserve in women. The ovarian reserve defines female reproductive lifespan, which in humans spans decades due to maintenance of meiotic arrest in oocytes residing in primordial follicles. The quality and quantity of oocytes are critical determinants for ovarian functions, and exhaustion of primordial follicles triggers menopause. However, our understanding how the ovarian reserve is generated and maintained is currently limited due to the inability to perform molecular analysis. In our unpublished study, we developed a protocol to isolate the pool of non-growing oocytes that enabled molecular analyses. We found that the Polycomb Repressive Complex 1 establishes repressive chromatin states in perinatal mouse oocytes that directly suppress the gene expression program of meiotic prophase-I and thereby enable the transition to dictyate arrest. Based on these findings, we propose that the chromatin state is established during perinatal oogenesis that enables ovarian reserve formation and then maintained in adult and aged ovaries. In Aim 1, we will perform a comprehensive chromatin profiling of the initial pools of non- growing oocytes from juvenile ovaries and the ovarian reserve maintained in adulthood. Aim 1 will establish an epigenome data resource of the ovarian reserve. In Aim2, we designed a candidate-based approach to define the regulatory mechanism of chromatin states in the ovarian reserve. We will determine the function of CHD4, a chromatin remodeler, in maintaining the ovarian reserve. Aim 2 will provide the foundation to investigate the chromatin-based maintenance mechanisms of the ovarian reserve. The proposed research will significantly advance the field by providing molecular insights how the epigenome of the ovarian reserve is established and maintained.