Epigenetic Regulation of Premature Ovarian Senescence by TAF4b

描述(申请人提供)：卵巢早衰或原发性卵巢功能不全的情况，影响1%的40岁以下的妇女，可由卵巢卵泡破裂或耗尽引起。含有总转录因子TFIID的TBP相关因子4b(TAF4b)最近在人类和小鼠中被认为是对生育至关重要的。TAF4b缺乏导致卵巢过早衰老的特征，包括不育症、卵母细胞质量差和基因表达显著变化。此外，初步数据显示，在缺乏TAF4b的新生儿卵巢中，原始卵泡加速枯竭，以及在枯竭之前表观遗传学的去调节。在出生时，TAF4b缺陷的卵巢似乎通过caspase 3依赖的细胞凋亡而丢失卵母细胞，这可能导致在生殖成熟小鼠中观察到的卵巢衰老。这项提案的目的是在体内和体外探索TAF4b通过转录调控卵母细胞表观基因组来对抗卵巢衰老的方式。目的1测试TAF4b在保存原始卵泡池中的卵母细胞自主作用。目的2探讨TAF4b在卵母细胞调控中的时间作用 负责该调控的表观基因组和转录靶标。这一建议将建立一种独特的小鼠模型，并更好地阐明卵泡维持和防止卵母细胞衰老和凋亡的分子机制。

DESCRIPTION (provided by applicant): The condition of premature ovarian aging, or primary ovarian insufficiency, affects 1% of women under the age of 40, and can be induced by ovarian follicle disruption or depletion. General transcription factor TFIID-contained TBP-associated factor 4b (TAF4b) has recently been implicated in both humans and mice as critically important for fertility. TAF4b deficiency results in hallmarks of premature ovarian aging, including infertilty, poor oocyte quality, and dramatic gene expression changes. In addition, preliminary data shows an accelerated depletion of primordial follicles in neonatal TAF4b deficient ovaries, as well as epigenetic deregulation prior to depletion. At birth, TAF4b deficient ovaries appear to lose oocytes through caspase 3-dependent apoptosis, which likely leads to the ovarian senescence observed in reproductively mature mice. The aims of this proposal will explore in vivo and in vitro the ways in which TAF4b opposes ovarian senescence by transcriptionally regulating the oocyte epigenome. Aim 1 will test the oocyte autonomous role of TAF4b in preserving the primordial follicle pool. Aim 2 will explore the temporal role of TAF4b in regulation of the oocyte epigenome and transcriptional targets responsible for that regulation. This proposal will establish a unique mouse model as well as better elucidate molecular mechanisms underlying ovarian follicle maintenance and prevention of oocyte senescence and apoptosis.