Ovarian-Specific Transcription Networks Regulated by the TFIID Subunit TAF4b

 描述（由申请人提供）：全世界约有1%的女性患有原发性卵巢功能不全（POI），这是由于卵泡储备减少导致的，通常会导致不孕。虽然在POI女性中发现了几个基因被破坏，但大约90%的病例不能归因于已知的遗传原因。通过揭示原始卵泡初始池发育及其在成年卵巢中维持的细胞和分子机制，我们将在不久的将来更好地理解，诊断和治疗POI。我们发现并鉴定了一种称为TAF 4 b的蛋白质，它对建立和维持小鼠的卵泡储备至关重要。TAF 4 b是一般转录因子TFIID的性腺富集亚基，TFIID是由TATA盒结合蛋白（TBP）和14种TBP相关因子（TAF）组成的大型多蛋白复合物。我们研究TAF 4 b对卵泡发育的调节的方法已经在TAF 4 b缺陷小鼠模型的背景下阐明了TAF 4 b的卵巢功能。总的来说，这些研究揭示了TAF 4 b缺陷型雌性小鼠患有POI的特征，包括持续发情、血清促卵泡激素（FSH）升高和原始卵泡加速耗竭。除了我们自己的工作之外，一些额外的研究已经将TAF 4 b在调节女性生育力中的潜在功能联系起来。总之，这些数据暗示了在人类POI的背景下TAF 4 b调节过程的潜在失调。基于在人类和小鼠中的这些互补研究，我们假设哺乳动物卵母细胞和卵巢中的TAF 4 b调节的转录事件有助于适当地维持正常的卵巢衰老和生育力。通过在这些研究中揭示TAF 4 b的卵巢下功能和机制，我们的目标是确定新的基因和表达机制，以确保在女性中成功生产高质量的卵母细胞，也许有一天可以更好地诊断和/或管理患有POI和其他相关卵巢健康缺陷的患者。

 DESCRIPTION (provided by applicant): Approximately 1% of the female population worldwide experiences primary ovarian insufficiency (POI) which results from a reduction of the ovarian follicle reserve that often leads to infertility. Although several genes have been found to be disrupted in women with POI, about 90% of the cases cannot be attributed to known genetic causes. By uncovering the cellular and molecular mechanisms underlying the development of the initial pool of primordial follicles and their maintenance in the adult ovary, we will be poise to better understand, diagnose and treat POI in the near future. We have discovered and characterized a protein called TAF4b that is essential for establishing and maintaining the ovarian follicle reserve in the mouse. TAF4b is a gonadal- enriched subunit of the general transcription factor TFIID, a large multiprotein complex composed of the TATA- box binding protein (TBP) and 14 TBP-associated factors (TAFs). Our approach to studying the regulation of ovarian follicle development by TAF4b has elucidated the ovarian functions of TAF4b in the context of a TAF4b-deficient mouse model. Collectively, these studies have revealed that TAF4b-deficient female mice suffer from hallmarks of POI including persistent estrous, elevated serum follicle stimulating hormone (FSH) and accelerated primordial follicle depletion. In addition to our own work, a number of additional studies have linked the potential function of TAF4b in the regulation of fertility in women. Together, these data implicate the potential deregulation of TAF4b-regulated processes in the context of human POI. Based on these complementary studies in humans and mice, we hypothesize that TAF4b-regulated transcriptional events in the mammalian oocyte and ovary serve to properly maintain normal ovarian aging and fertility. By uncovering the sub-ovarian functions and mechanisms of TAF4b in these studies, we aim to identify novel genes and expression mechanisms in place to ensure the successful production of high quality oocytes in women and perhaps one day better diagnose and/or manage patients with POI and other related deficits of ovarian health.