Kim Jeesun, Singh Anup Kumar, Takata Yoko, Lin Kevin, Shen Jianjun, Lu Yue, Kerenyi Marc A, Orkin Stuart H, Chen Taiping
Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, 1808 Park Road 1C, Smithville, Texas 78957, USA.
Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Science Park, 1808 Park Road 1C, Smithville, Texas 78957, USA.
Nat Commun. 2015 Dec 2;6:10116. doi: 10.1038/ncomms10116.
Mammalian oocytes are arrested at prophase I until puberty when hormonal signals induce the resumption of meiosis I and progression to meiosis II. Meiotic progression is controlled by CDK1 activity and is accompanied by dynamic epigenetic changes. Although the signalling pathways regulating CDK1 activity are well defined, the functional significance of epigenetic changes remains largely unknown. Here we show that LSD1, a lysine demethylase, regulates histone H3 lysine 4 di-methylation (H3K4me2) in mouse oocytes and is essential for meiotic progression. Conditional deletion of Lsd1 in growing oocytes results in precocious resumption of meiosis and spindle and chromosomal abnormalities. Consequently, most Lsd1-null oocytes fail to complete meiosis I and undergo apoptosis. Mechanistically, upregulation of CDC25B, a phosphatase that activates CDK1, is responsible for precocious meiotic resumption and also contributes to subsequent spindle and chromosomal defects. Our findings uncover a functional link between LSD1 and the major signalling pathway governing meiotic progression.
哺乳动物卵母细胞在减数分裂前期I停滞，直至青春期，此时激素信号诱导减数分裂I恢复并进入减数分裂II。减数分裂进程由CDK1活性控制，并伴随着动态的表观遗传变化。尽管调节CDK1活性的信号通路已明确，但表观遗传变化的功能意义仍大多未知。在此，我们表明赖氨酸去甲基化酶LSD1调节小鼠卵母细胞中的组蛋白H3赖氨酸4二甲基化（H3K4me2），并且对减数分裂进程至关重要。在生长中的卵母细胞中条件性删除Lsd1会导致减数分裂过早恢复以及纺锤体和染色体异常。因此，大多数缺失Lsd1的卵母细胞无法完成减数分裂I并发生凋亡。从机制上讲，激活CDK1的磷酸酶CDC25B的上调导致减数分裂过早恢复，并且还导致随后的纺锤体和染色体缺陷。我们的发现揭示了LSD1与控制减数分裂进程的主要信号通路之间的功能联系。
