The methyltransferase Setdb1 is essential for meiosis and mitosis in mouse oocytes and early embryo

Oocytes develop the competence for meiosis and early embryogenesis during their growth. Setdb1 is a histone H3 lysine 9 (H3K9) methyltransferase required for post-implantation development and has been implicated in the transcriptional silencing of genes and endogenous retroviral elements (ERVs). To address its role in oogenesis and pre-implantation development, we conditionally deleted Setdb1 in growing oocytes. Loss of Setdb1 expression greatly impaired meiosis. It delayed meiotic resumption, altered the dynamics of chromatin condensation, and impaired kinetochore-spindle interactions, bipolar spindle organization, and chromosome segregation in more mature oocytes. The observed phenotypes related to changes in abundance of specific transcripts in mutant oocytes. Setdb1 maternally deficient embryos arrested during pre-implantation development and showed comparable defects during cell cycle progression and in chromosome segregation. Finally, transcriptional profiling data indicate that Setdb1 down-regulates rather than silences expression of ERVK and ERVL-MaLR retrotransposons and associated chimeric transcripts during oogenesis. Our results identify Setdb1 as a novel meiotic and embryonic competence factor in meiosis and mitosis, safeguarding genome integrity at the onset of life. We performed expression profiling on pools of 16 denuded GV-oocytes isolated per mouse. We used oocytes from 4 Setdb1 f/+; Zp3-cre mice and 2 Setdb1 f/- mice as controls and oocytes from 4 Setdb1 f/-; Zp3-cre mice as mutant.卵母细胞在生长阶段获得减数分裂与早期胚胎发育的潜能。Setdb1是一种组蛋白H3赖氨酸9（H3K9）甲基转移酶，为植入后发育所必需，且参与基因与内源性逆转录病毒元件（ERVs）的转录沉默调控。为阐明Setdb1在卵子发生与植入前发育中的调控功能，我们对生长中的卵母细胞条件性敲除Setdb1基因。Setdb1表达缺失会严重损害减数分裂进程：该缺失会延迟减数分裂恢复、改变染色质凝缩动态，并影响成熟卵母细胞的动粒-纺锤体相互作用、双极纺锤体组装与染色体分离。所观测到的表型与突变卵母细胞内特定转录本的丰度改变显著相关。母体Setdb1缺陷的胚胎会在植入前发育阶段停滞，并在细胞周期进程与染色体分离过程中出现相似缺陷。最后，转录组分析数据显示，在卵子发生过程中，Setdb1并非沉默而是下调ERVK、ERVL-MaLR逆转录转座子及相关嵌合转录本的表达。本研究结果证实Setdb1是一类全新的减数分裂与有丝分裂时期的发育潜能因子，在生命起源之初维系基因组完整性。我们对每只小鼠分离得到的16枚裸生发泡卵母细胞（denuded GV-oocytes）混合样本进行了表达谱分析。对照组使用4只Setdb1 f/+; Zp3-cre小鼠与2只Setdb1 f/-小鼠的卵母细胞，突变组则使用4只Setdb1 f/-; Zp3-cre小鼠的卵母细胞。