Ovarian-Specific Transcription Networks Regulated by the TFIID Subunit TAF4b

 描述(由申请人提供)：全世界大约1%的女性经历了原发性卵巢功能不全(POI)，这是由于卵巢卵泡储备减少而导致的，这通常会导致不孕。尽管已发现POI妇女中有几个基因被破坏，但约90%的病例不能归因于已知的遗传原因。通过揭示原始卵泡池的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。我们已经发现并鉴定了一种名为TAF4b的蛋白质，它对于建立和维持小鼠的卵巢卵泡储备至关重要。TAF4b是一般转录因子TFIID的性腺富集亚单位，TFIID是由TATA盒结合蛋白(TBP)和14个TBP相关因子(TAFs)组成的大型多蛋白复合体。我们研究TAF4b对卵泡发育的调节的方法已经阐明了TAF4b在TAF4b缺陷小鼠模型中的卵巢功能。总而言之，这些研究表明，TAF4b基因缺陷的雌性小鼠患有POI的特征，包括持续发情、血清卵泡刺激素(FSH)升高和加速原始卵泡枯竭。除了我们自己的工作外，一些额外的研究也将TAF4b在调节女性生育方面的潜在功能联系在一起。总之，这些数据暗示了在人类POI的背景下，TAF4b调节的过程可能会放松管制。基于对人类和小鼠的这些互补性研究，我们假设TAF4b调控的哺乳动物卵母细胞和卵巢中的转录事件有助于适当地维持正常的卵巢衰老和生育。通过在这些研究中揭示TAF4b的亚卵巢功能和机制，我们的目标是确定新的基因和表达机制，以确保女性成功生产高质量的卵母细胞，并可能有一天更好地诊断和/或处理POI和其他相关的卵巢健康缺陷患者。

 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.