组蛋白H3.3变体在小鼠早期胚胎组蛋白修饰遗传与重编程中的作用与机制研究

组蛋白修饰的继承和重塑在胚胎全能性获得和细胞命运决定中发挥重要作用。申请人前期在Nature、NCB等杂志上发表成果，解析了小鼠植入前胚胎多种组蛋白修饰的变化规律,但是目前为止对早期胚胎组蛋白修饰调控机制的研究还十分有限，而父源和母源基因组上的组蛋白修饰如何选择性地遗传给后代也并不清楚。组蛋白变体H3.3在早期胚胎发育中的作用十分关键并且可能参与组蛋白修饰继承和重编程的调控。本项目中，我们将结合课题组成熟的胚胎显微操作和微量测序技术，利用HA-H3.3标记的小鼠，1）解析H3.3在早期胚胎发育过程中对组蛋白修饰重编程的调控机制，2）探讨H3.3在父母源基因组上组蛋白修饰继承和重编程中的作用。目前我们已经获得了H3.3在早期胚胎中的变化数据，初步的分析证实H3K27me3修饰的变化与H3.3的变化有明显的相关性，该项目的研究将从组蛋白变体调控的角度解析组蛋白修饰遗传和重编程的分子机制。

Inheritance and reprogramming of histone modifications are important for totipotency acquisition and cell fate determination. The applicant reveals the reprogramming pattern of histone modification during early embryonic development in previous research and published in journals including Nature, Nature Cell Biology et al. But the function and mechanism of this process remain unclear, and how the histone modification in paternal and maternal genome is transmitted during fertilization still need further investigation. Histone H3.3 variants is a critical factor during early embryo development and replaced after fertilization. Regulation of H3.3 may be responsible for the inheritance and reprogramming of histone modifications but the mechanism is still unknown. Thus in this study, utilizing the HA-H3.3 transgenetic mouse and the mature embryo micromanipulation and micro cell sequencing technology, we intend to 1) investigate the mechanism of histone modification reprogramming by H3.3 during mouse early embryo development, 2) discuss the function of H3.3 during histone modification inheritance and reprogramming in paternal and maternal genome. Our ongoing experiments confirmed that the dynamic of histone H3K27me3 modification is correlated with the changes of H3.3 varients. Finding of this study will elucidate the mechanism of the inheritance and reprogramming of histone modification from the point of histone variants regulation.