Epigenetic Regulation of Premature Ovarian Senescence by TAF4b

描述（由申请人提供）：卵巢早衰，或原发性卵巢功能不全，影响1%的40岁以下女性，可由卵巢卵泡破坏或衰竭引起。包含tfiid的一般转录因子tbp相关因子4b （TAF4b）最近在人类和小鼠中都被认为对生育至关重要。TAF4b缺乏导致卵巢早衰的特征，包括不孕、卵母细胞质量差和剧烈的基因表达变化。此外，初步数据显示，在TAF4b缺陷的新生儿卵巢中，原始卵泡的消耗加速，以及在消耗之前的表观遗传失调。出生时，TAF4b缺陷卵巢似乎通过caspase 3依赖性凋亡失去卵母细胞，这可能导致在生殖成熟小鼠中观察到的卵巢衰老。本提案的目的是在体内和体外探索TAF4b通过转录调节卵母细胞表观基因组来对抗卵巢衰老的方式。目的1将测试TAF4b在保存原始卵泡池中的卵母细胞自主作用。目的2将探讨TAF4b在卵母细胞调控中的时间作用

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.