Epigenetic Regulation of Premature Ovarian Senescence by TAF4b

TAF4b 对卵巢早衰的表观遗传调控

• 批准号: 8737721
• 负责人: Kathryn J Grive
• 金额: $ 4.27万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2016-10-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8737721
• 关键词: Affect; Age; Aging; Aging-Related Process; Aneuploidy; Apoptosis; Biology; Birth; Cells; Chromosomes; Competence; Coupled; Data; Defect; Development; Diagnostic; Disease; Embryo; Embryonic Development; Epigenetic Process; Exercise; Exhibits; Fertility; Fertilization in Vitro; Gene Expression; Gene Expression Profile; General Transcription Factors; Genes; Genetic Transcription; Genome; Genomics; Germ Cells; Goals; Histone Acetylation; Histones; Homeostasis; Human; Immunofluorescence Immunologic; In Vitro; Infertility; Injection of therapeutic agent; Maintenance; Meiotic Prophase I; Modification; Molecular; Mus; Neonatal; Oocytes; Ovarian; Ovarian Follicle; Ovary; Pattern; Play; Prevention; Primates; Primordial Follicle; Regulation; Research; Role; Staging; Supporting Cell; Testing; Time; Tissues; Transcription Factor TFIID; Turner' s Syndrome; Vesicle; Woman; aged; body system; caspase-3; chromatin immunoprecipitation; chromatin remodeling; epigenome; genome wide association study; histone modification; human TAF1 protein; in vivo; mouse model; novel; premature; prevent; public health relevance; reproductive; senescence; sperm cell; tool; transcription factor

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.

描述（由申请人提供）：卵巢早衰或原发性卵巢功能不全的状况影响1%的40岁以下女性，并且可以由卵泡破坏或耗竭引起。一般转录因子TFIID包含TBP相关因子4b（TAF4b）最近被认为在人类和小鼠中对生育力至关重要。TAF4b缺乏导致卵巢早衰的标志，包括不育，卵母细胞质量差和显著的基因表达变化。此外，初步数据显示，新生儿TAF 4b缺陷卵巢中原始卵泡的加速消耗，以及消耗前的表观遗传失调。在出生时，TAF4b缺陷卵巢似乎通过半胱天冬酶3依赖性细胞凋亡失去卵母细胞，这可能导致在生殖成熟小鼠中观察到的卵巢衰老。该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对抗卵巢衰老的方式。目的1检测TAF4b在保存原始卵泡池中的自主作用。目的2探讨TAF4b在卵母细胞发育调控中的作用 表观基因组和转录靶点负责该调节。这一建议将建立一个独特的小鼠模型，以及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。