Stella's Role in Oocyte DNA Methylation Suggests Additional Activities of DNMT1.
Stella's Role in Oocyte DNA Methylation Suggests Additional Activities of DNMT1.
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DOI：
10.1021/acs.biochem.9b00146
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发表时间：
2019-03
期刊：
影响因子：
2.9
通讯作者：
Lea Kiefer;M. Simon
中科院分区：
文献类型：
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作者：
Lea Kiefer;M. Simon
DNA 甲基化是可遗传的共价修饰的原型，可以调节基因表达。 DNA 甲基化通过复制得以维持，主要是由于 DNA 甲基转移酶 DNMT1 的酶活性，DNMT1 负责甲基化新生成的（半甲基化）DNA，以确保 DNA 甲基化位点的忠实遗传。与体细胞相对稳定的模式不同，DNA 甲基化在配子成熟和早期胚胎发生过程中发生了巨大的重塑。精子 DNA 是高甲基化的，而卵母细胞中的 DNA 大部分是低甲基化的，并且这些各自水平的 DNA 甲基化对于成功受精（受精卵形成）和早期胚胎发生是必需的。最近，人们对卵母细胞维持低甲基化状态的过程有了新的认识。在《自然》杂志最近发表的一篇文章中，Li 等人。证明发育因子 Stella 通过从小鼠卵母细胞的细胞核输出甲基化机制来抑制 Dnmt1 的功能。作者表明，Stella 对于正确的受精卵形成很重要。作者出乎意料地发现，结果还支持了这样的假设：维持甲基转移酶 Dnmt1 还具有作为从头 DNA 甲基转移酶的额外作用。 1哺乳动物 DNA 甲基化，特别是 5 位胞嘧啶 (5mC) 的甲基化，参与发育过程中基因表达的调节，并且对于基因组印记和基因组中重复元件的沉默至关重要。 5mC 主要在 CpG 二核苷酸中发现，估计大多数 CpG 在体细胞中被甲基化。 2 哺乳动物 DNA 甲基化由三种甲基转移酶实现：DNMT1、DNMT3A 和 DNMT3B。其中，DNMT3A 和 DNMT3B 被认为是从头甲基转移酶，而 DNMT1 在 DNA 复制过程中充当维持甲基转移酶。 5mC 通过 DNA 复制的传播涉及半甲基化 DNA 的识别，其中一条链具有甲基化（亲本），而另一条链则未甲基化（新合成的子链）。半甲基化 DNA 可被 UHRF1（也称为 NP95）等因子识别。 UHRF1 特异性结合甲基化亲本链，引导 DNMT1 甲基化子链，从而帮助忠实地传播表观遗传标记。 DNMT1 或 UHRF1 的缺失会导致胚胎致死和甲基化的整体减少。 3 虽然 DNA 甲基化的分布在体细胞中保持相对恒定，但生殖细胞的 DNA 甲基化经历了大规模的变化，无论是在早期胚胎发生期间 4 通过广泛的去甲基化还是在配子形成期间。精子细胞在产前变得高度甲基化，但在产后迅速去甲基化
DNA methylation is the archetype of a heritable covalent modification that can regulate gene expression. DNA methylation is maintained through replication due primarily to the enzymatic activity of the DNA methyltransferase DNMT1, which is responsible for methylating newly made (hemimethylated) DNA to ensure faithful inheritance of sites of DNA methylation. Unlike the relatively stable patterns of somatic cells, DNA methylation is dramatically remodeled during gamete maturation and early embryogenesis. Sperm DNA is hypermethylated, whereas DNA in oocytes is largely hypomethylated, and these respective levels of DNA methylation are necessary for successful fertilization (zygote formation) and early embryogenesis. New insight into the process, by which oocytes maintain a generally hypomethylated state, has recently been uncovered. In a recent publication in Nature, Li et al. demonstrated that the developmental factor Stella inhibits the function of Dnmt1 by exporting methylation machinery from the nucleus in mouse oocytes. The authors show that Stella is important for correct zygote formation. As an unexpected twist, the authors, results also support the hypothesis that the maintenance methyltransferase Dnmt1 has additional roles as a de novo DNA methyltransferase. 1Mammalian DNA methylation, specifically the methylation of cytosines at position 5 (5mC), is involved in regulating gene expression during development and is central to genomic imprinting and the silencing of repetitive elements in the genome. 5mC is primarily found in the context of CpG dinucleotides, and it is estimated that the majority of CpGs are methylated in somatic cells. 2 Mammalian DNA methylation is installed by three methyltransferases: DNMT1, DNMT3A, and DNMT3B. Of these, DNMT3A and DNMT3B are considered the de novo methyltransferases, while DNMT1 acts as the maintenance methyltransferase during DNA replication. The propagation of 5mC through DNA replication involves recognition of hemimethylated DNA, where one strand bears methylation (parental), while the other is unmethylated (the newly synthesized daughter strand). Hemimethylated DNA is recognized by factors including UHRF1 (also known as NP95). UHRF1 specifically binds the methylated parental strand guiding DNMT1 to methylate the daughter strand thereby helping to faithfully propagate the epigenetic mark. Loss of either DNMT1 or UHRF1 causes embryonic lethality and global reduction of methylation. 3 While distribution of DNA methylation remains relatively constant in somatic cells, germ cells undergo large scale changes in DNA methylation, both during early embryogenesis 4 through extensive demethylation and during gamete formation. Sperm cells become hypermethylated prenatally, yet quickly demethylate during