HDAC3在小鼠卵母细胞发育中的作用及机制研究

A major cause of infertility, miscarriage and birth defects is impaired quality of oocyte. As an important epigenetic enzyme, HDAC3 is involved in multiple physiological and pathological processes. However, its role during oocyte meiosis remains unknown. Our preliminary data has shown that in mouse oocytes, in vitro knockdown of HDAC3 by specific siRNA injection leads to the arrest of meiotic maturation, spindle defects and chromosome congression failure. The frequency of kinetochore-microtubule mis-attachments and aneuploidy is also increased significantly, with hyperacetylated tubulin. These results indicate that HDAC3 is involved in the regulation of oocyte maturation, and tubulin might be a critical substrate of HDAC3. In this project, we decide to explore how HDAC3 regulates oocyte development by employing the conditional knockout mouse model. Our findings will make a contribution for improving oocyte quality and reducing birth defects.

导致不孕不育、自然流产和出生缺陷的一个重要因素是女性卵子质量低劣。组蛋白去乙酰化酶3(Histone deacetylase 3,HDAC3)是一种参与多种生理和病理过程的蛋白质表观修饰酶。但是，HDAC3在卵母细胞发育成熟过程中的作用尚不清楚。我们的前期工作表明，通过体外HDAC3特异敲减的方法，发现降低HDAC3表达水平导致了小鼠卵母细胞成熟受阻、染色体排列错误和纺锤体组装缺。而且，动粒微管的附着和核型的异常率也都显著升高，特别是诱导了超乙酰化的微管蛋白。这些结果暗示HDAC3参与了卵母细胞的成熟过程，而微管蛋白则可能是其关键底物。本项目拟进一步应用卵母细胞特异性敲除小鼠模型，深入揭示体内HDAC3调控卵母细胞发育的分子机制，为改善卵子质量和降低出生缺陷提供理论基础和分子靶标。

卵母细胞发育是雌性生殖过程的重要环节之一，而减数分裂异常是造成卵子质量下降的关键因素。组蛋白去乙酰化酶3（HDAC3）是一种普遍存在的蛋白，人们对于其在卵母细胞成熟过程中的作用还一无所知。我们的前期工作发现，HDAC3敲减的卵母细胞出现纺锤体组装缺陷和染色体排列错误的表型，动粒微管相互作用的异常比率显著增加，并且导致卵子非整倍性升高。我们推测HDAC3通过控制底物蛋白的乙酰化水平，改变动粒-微管相互作用，最终调控卵母细胞中纺锤体组装和染色体运动等减数分裂活动。本项目拟应用条件性敲除小鼠在体模型，进一步深入探讨HDAC3在卵母细胞发育成熟过程中的作用及机制，为了解卵母细胞发育调控网络和改善卵子质量提供新的思路和途径。