针对DNA甲基转移酶基因的向突变导致胚胎死亡
1Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142.
Cell
|June 12, 1992
概括
基因向创造了缺乏DNA甲基转移酶的小鼠. 虽然胚胎干细胞存活下来,但同卵性突变胚胎表现出发育延迟和致命性,这表明DNA甲基化.
科学领域:
- 表观遗传学和基因调控
- 发展生物学 发展生物学
- 遗传学和基因组学 遗传学和基因组学
背景情况:
- 基因甲基化对哺乳动物发育至关重要.
- DNA甲基转移酶 (DNMT) 是负责DNA甲基化的主要酶.
- 了解DNMT在体内的作用对于发育研究至关重要.
研究的目的:
- 通过创建一个淘汰赛小鼠模型来研究DNA甲基转移酶 (DNMT) 的体内功能.
- 确定减少基因组DNA甲基化对胚胎发育和细胞活力的后果.
主要方法:
- 在胚胎干细胞 (ES) 中准基因,以破坏小鼠DNA甲基转移酶基因.
- 生成同卵性突变ES细胞系并分析DNA甲基转移酶活性和DNA甲基化水平.
- 将突变引入小鼠生殖线,以评估胚胎死亡率和发育异常.
主要成果:
- 同卵性突变ES细胞表现出微量DNA甲基转移酶活性和基因组5甲基酸 (m5C) 水平的3倍降低,对细胞活力或形态没有影响.
- 南方斑点分析显示,ES细胞突变中的内源逆转录病毒DNA脱甲基化.
- 该突变的生殖系传播导致同卵子胚胎的生长迟缓,发育迟缓,并在妊娠中期时导致胚胎死亡.
- 同卵性胚胎显示m5C水平的降低与ES细胞中观察到的类似.
结论:
- 基因组DNA甲基化显著减少与胚胎干细胞在体外生存能力相兼容.
- 然而,胚胎发育期间DNA甲基化的类似减少会导致严重的发育异常和致命性.
- 这些发现突出了DNA甲基化在哺乳动物胚胎发生过程中的关键和上下文依赖的作用.
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