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Uhrf2基因缺失致卵泡发育异常的分子基础及机制研究

批准号31701303 学科分类女(雌)性生殖细胞 ( C120203 )
项目负责人潘鸿捷 负责人职称助理研究员 依托单位上海市计划生育科学研究所
资助金额20.00
万元
项目类别青年科学基金项目 研究期限2018 年 01 月 01 日 至
2020 年 12 月 31 日
中文主题词小鼠;DNA修饰;颗粒细胞;卵泡成熟
英文主题词mouse;DNA modification;granulosa cell;follicle maturation

摘要

中文摘要 在卵泡发育过程中, 颗粒细胞的形态和功能发生了显著的变化,基因表达谱也随之改变。DNA修饰可以从染色质上改变DNA构型,并影响多个基因的表达。然而在颗粒细胞中,DNA整体水平修饰变化如何影响颗粒细胞发育及功能,目前的报道还十分有限。我们发现UHRF2定位于卵巢颗粒细胞。UHRF2被报道能特异性识别5hmc,同时也参与DNA半甲基化到全甲基化的转变,以及组蛋白的修饰。本实验构建了UHRF2基因敲除鼠。敲除雌鼠出现生育力下降,卵子释放数量减小,动情周期延长,闭锁卵泡增多等多个表型。这些卵巢功能缺陷以及UHRF2的特殊定位暗示UHRF2缺失导致颗粒细胞异常。本项目研究UHRF2对颗粒细胞发育及功能的影响,并拟阐明UHRF2对DNA-5hmc可能的调控机理。通过本项目的研究,可以加深对颗粒细胞表观调控的认识,并最终为预防、诊断和治疗颗粒细胞异常引起的雌性不育提供理论支撑。
英文摘要 Granulosa cell is essential for oocytes growth, maturation and ovulation. The gene expression in granulosa cells as well as morphology and function alters as the development of the follicle. The modification of genomic DNA changes the conformation of chromatins as well as the expression of a series of related genes. However, the research of how DNA modification alters the development and function of granulosa cells is limited. Herein, we found UHRF2 expressed in granulosa cells. The Uhrf2, which is similar to Uhrf1, is an essential cofactor of maintenance DNA methylation. Binding assays demonstrate a cooperative interplay of Uhrf2 domains that induces preference for hemi-methylated DNA, the substrate of maintenance methylation, and enhances binding to H3K9me3 heterochromatin marks. We established the Uhrf2 knockout mouse by the method of gene trap. The fertility, as well as ovulation was down-regulated in the knockout females. The estrous cycle was prolonged and more atretic follicles were found in the female knockout mouse. The deficient function of ovary, together with the special localization of UHRF2 indicated the deficiency of granulosa cell. This project will study how UHRF2 knock out leads to the deficient development and function in granulosa cells. In mechanism, we will try to elucidate how UHRF2 regulates DNA-5hmc. In summary,our research will be helpful for providing a new prospect that how granulosa cell influences follicle in ovary.
结题摘要

成果

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