H2A组蛋白的泛素化修饰对胚胎干细胞的染色质结构调节及基因表达调控都具有非常重要的作用。但是，在干细胞干性维持、分化及细胞重编程的过程中H2A的泛素化修饰是如何被精细地调控的仍然不清楚。在前期的研究中，我们发现在小鼠胚胎干细胞中抑制去泛素化酶USP21的表达能够显著上调H2AK119位的泛素化，并且促进小鼠胚胎干细胞分化。 在USP21敲除的MEF细胞中，诱导其形成iPSC的效率也明显下调。这些结果提示USP21在胚胎干细胞干性维持及细胞重编程过程中起着重要的作用。在此基础上，本申请拟继续深入研究USP21去泛素化酶活性对H2A泛素化的调控、染色质结构的调控以及对小鼠胚胎干细胞自我更新和维持其未分化状态的下游分子机制，并探讨其在体细胞重编程过程中对表观遗传机制的调控机制。本项目的实施将有助于进一步理解去泛素化酶USP21的生物功能及参与表观遗传调控机制的研究。

Monoubiquitination of H2A plays an essential role in chromatin remodeling and gene expression of embryonic stem cells. However, the underlying mechanism by which H2A is deubiquitinated remains unknown. In our preliminary data, we found that knockdown of deubiquitinase USP21 in mESCs results in the upregulation of H2A monoubiquitination at K119 and mESC differentiation. Moreover, comparing to wild-type MEFs, the efficiency of reprogramming USP21 knockout MEFs to ES cells was dramatically decreased. These data indicate that USP21 is essential for mESC stemness maintainace and reprogramming. Here, we plan to further study the function and molecular mechanism of USP21 regulating H2A deubiquitination, chromatin remodeling, self-renewal of mESCs and reprogramming MEFs to mESCs. This study will uncover the regulatory mechanism of H2A deubiquitination and USP21 function in mESC, reprogramming and epigenetics.