DNMT3A ADD 域是有效的 de novo DNA 甲基化和在小鼠卵细胞中的母性印记所必需的
Ryuji Uehara1, Wan Kin Au Yeung1, Keisuke Toriyama1
1Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
PLoS genetics
|August 1, 2023
概括
在DNA甲基转移酶DNMT3A的ADD域中的突变破坏了卵细胞DNA甲基化,导致发育缺陷和小鼠的表观遗传遗传. 这凸显了ADD域在新甲基化中的关键作用.
科学领域:
- 表观遗传学和基因组学
- 发展生物学 发展生物学
- 哺乳动物繁殖 哺乳动物繁殖
背景情况:
- 适当的DNA甲基化对于哺乳动物卵细胞功能,印记和胚胎发育至关重要.
- 在卵细胞中,新型DNA甲基化主要由DNA甲基转移酶DNMT3A进行介导.
- DNMT3A的ATRX-DNMT3-DNMT3L (ADD) 域与非甲基化组素H3 lysine 4 (H3K4me0) 相互作用,以调节其活性.
研究的目的:
- 调查DNMT3A介导的新基因甲基化中ADD域-希斯相互作用的体内功能.
- 阐明ADD域功能受损对卵细胞甲基化和胚胎发育的影响.
主要方法:
- 用DNMT3A.的ADD域中氨基酸替代生成的小鼠.
- 在卵细胞和胚胎中分析了DNA甲基化模式 (CG和非CG).
- 评估胚胎活力,印记控制区域甲基化和基因表达.
主要成果:
- 在DNMT3AADD域的突变导致卵细胞的矮化和严重的甲基化缺陷,包括CG甲基化的马赛克损失和非CG甲基化的几乎完全损失.
- 来自受影响卵细胞的胚胎表现出妊娠中期到晚期的致死性,其特点是随机的,在印记区域和基因误表达中完全或完全失去CG甲基化.
- 甲基化损失发生在分裂阶段的胚胎中,植入后部分恢复,这表明两步表观遗传过程.
结论:
- 在哺乳动物卵细胞中,ADD域对于高效且过程性的de novoCG甲基化至关重要.
- 缺陷的ADD域功能导致严重的表观遗传乱和发育失败.
- 这项研究为跨代表观遗传错误的随机遗传提供了一个模型.
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