Xu Kai, Chen Xia, Yang Hui, Xu Yiwen, He Yuanlin, Wang Chenfei, Huang Hua, Liu Baodong, Liu Wenqiang, Li Jingyi, Kou Xiaochen, Zhao Yanhong, Zhao Kun, Zhang Linfeng, Hou Zhenzhen, Wang Hong, Wang Hailin, Li Jing, Fan Hengyu, Wang Fengchao, Gao Yawei, Zhang Yong, Chen Jiayu, Gao Shaorong
From the Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
the Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou 310058, China.
J Biol Chem. 2017 Feb 3;292(5):1798-1807. doi: 10.1074/jbc.M116.767061. Epub 2016 Dec 28.
Sall4 (Splat-like 4) plays important roles in maintaining pluripotency of embryonic stem cells and in various developmental processes. Here, we find that Sall4 is highly expressed in oocytes and early embryos. To investigate the roles of SALL4 in oogenesis, we generated Sall4 maternal specific knock-out mice by using CRISPR/Cas9 system, and we find that the maternal deletion of Sall4 causes developmental arrest of oocytes at germinal vesicle stage with non-surrounded nucleus, and the subsequent meiosis resumption is prohibited. We further discover that the loss of maternal Sall4 causes failure in establishment of DNA methylation in oocytes. Furthermore, we find that Sall4 modulates H3K4me3 and H3K27me3 modifications by regulating the expression of key histone demethylases coding genes Kdm5b, Kdm6a, and Kdm6b in oocytes. Moreover, we demonstrate that the aberrant H3K4me3 and H3K27me3 cause mis-expression of genes that are critical for oocytes maturation and meiosis resumption. Taken together, our study explores a pivotal role of Sall4 in regulating epigenetic maturation of mouse oocytes.
Sall4（类Splat 4）在维持胚胎干细胞的多能性以及各种发育过程中发挥着重要作用。在此，我们发现Sall4在卵母细胞和早期胚胎中高度表达。为了研究SALL4在卵子发生中的作用，我们利用CRISPR/Cas9系统构建了Sall4母源特异性敲除小鼠，并且发现母源缺失Sall4会导致卵母细胞在生发泡期发育停滞，核周无核，随后减数分裂恢复被抑制。我们进一步发现母源Sall4缺失会导致卵母细胞中DNA甲基化建立失败。此外，我们发现Sall4通过调控卵母细胞中关键组蛋白去甲基化酶编码基因Kdm5b、Kdm6a和Kdm6b的表达来调节H3K4me3和H3K27me3修饰。而且，我们证明异常的H3K4me3和H3K27me3会导致对卵母细胞成熟和减数分裂恢复至关重要的基因表达错误。综上所述，我们的研究探索了Sall4在调节小鼠卵母细胞表观遗传成熟中的关键作用。
