Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1
Stella safeguards the oocyte methylome by preventing de novo methylation mediated by DNMT1
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Stella 通过阻止 DNMT1 介导的从头甲基化来保护卵母细胞甲基化。
DOI：
10.1038/s41586-018-0751-5
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发表时间：
2018-12-06
期刊：
影响因子：
64.8
通讯作者：
Zhu, Bing
中科院分区：
文献类型：
--
作者：
Li, Yingfeng;Zhang, Zhuqiang;Zhu, Bing
哺乳动物卵母细胞的出生后生长伴随着 DNA 甲基化的逐渐增加，这主要由 DNMT3A（一种从头 DNA 甲基转移酶）介导(1,2)。与精子和大多数体细胞的基因组不同，卵母细胞基因组在转录惰性区域低甲基化(2-4)。然而，卵母细胞甲基化组的这种独特特征是如何确定的以及它对早期胚胎发育能力的贡献仍然很大程度上未知。在这里，我们证明了 Stella（女性生育能力必需的因素 (5-7)）在塑造小鼠卵母细胞甲基化组方面的重要性。缺乏Stella的卵母细胞在全基因组水平上获得过度的DNA甲基化，包括在非活性基因的启动子中。这种异常的高甲基化部分是由两细胞阶段的胚胎遗传的，并损害合子基因组的激活。从机制上讲，Stella 的缺失会导致 DNA 甲基化调节因子 UHRF1(8,9) 异位核积聚，从而导致维持性 DNA 甲基转移酶 DNMT1 在细胞核中错误定位。遗传分析证实了 UHRF1 和 DNMT1 在 Stella 缺陷卵母细胞中产生异常 DNA 甲基化组中的主要作用。因此，Stella 通过防止 DNMT1 和 UHRF1 介导的异常 DNA 从头甲基化来保护独特的卵母细胞表观基因组。
Postnatal growth of mammalian oocytes is accompanied by a progressive gain of DNA methylation, which is predominantly mediated by DNMT3A, a de novo DNA methyltransferase(1,2). Unlike the genome of sperm and most somatic cells, the oocyte genome is hypomethylated in transcriptionally inert regions(2-4). However, how such a unique feature of the oocyte methylome is determined and its contribution to the developmental competence of the early embryo remains largely unknown. Here we demonstrate the importance of Stella, a factor essential for female fertility(5-7), in shaping the oocyte methylome in mice. Oocytes that lack Stella acquire excessive DNA methylation at the genome-wide level, including in the promoters of inactive genes. Such aberrant hypermethylation is partially inherited by two-cell-stage embryos and impairs zygotic genome activation. Mechanistically, the loss of Stella leads to ectopic nuclear accumulation of the DNA methylation regulator UHRF1(8,9), which results in the mislocalization of maintenance DNA methyltransferase DNMT1 in the nucleus. Genetic analysis confirmed the primary role of UHRF1 and DNMT1 in generating the aberrant DNA methylome in Stella-deficient oocytes. Stella therefore safeguards the unique oocyte epigenome by preventing aberrant de novo DNA methylation mediated by DNMT1 and UHRF1.