Nucleomethylin deficiency impairs embryonic erythropoiesis
Nucleomethylin deficiency impairs embryonic erythropoiesis
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核甲基化缺陷损害胚胎红细胞生成
DOI：
10.1093/jb/mvx086
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Motohashi Hozumi
中科院分区：
文献类型：
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作者：
Murakami Shohei;Suzuki Takuma;Yokoyama Wataru;Yagi Satoko;Matsumura Keita;Nakajima Yuka;Harigae Hideo;Fukamizu Akiyoshi;Motohashi Hozumi
核甲基素（NML）通过调节rRNA的转录和转录后修饰参与核糖体的形成。基于NML-/-小鼠常发生胚胎致死的现象，我们对NML-/-小鼠胚胎进行了分析，以阐明NML在胚胎发生中的作用。我们发现NML缺陷导致E10.5和E12.5之间的时间点的致死性。大多数E10.5NML-/-胚胎表现为生长迟缓和/或畸形，红细胞生成明显受损。与先前的研究一致，28 S rRNA中的m1A在NML-/-胎肝（FL）细胞中显著减少。由于先前的研究表明NML敲低细胞的p53依赖性凋亡，并且由于我们观察到NML-/-FL细胞中p53靶基因之一p21的上调，我们测试了p53破坏是否消除了NML缺陷表型。与我们的预期相反，抑制p53并不能挽救NML-/-胚胎的致死性或受损的红细胞生成，这表明NML缺陷表型的基础是p53非依赖性机制。这些结果阐明了NML在胚胎发生过程中，特别是在红细胞生成中的重要作用。我们推测，胚胎红细胞生成对蛋白质合成受损特别敏感，这是由rRNA甲基化缺陷和随后的核糖体形成失败引起的。
Nucleomethylin (NML) has been shown to contribute to ribosome formation through regulating transcription and post-transcriptional modification of rRNA. Based on the observation thatNML–/–mice are frequently embryonic lethal, we analyzedNML–/–embryos to clarify the role of NML in embryogenesis. We found thatNMLdeficiency leads to lethality at the time point between E10.5 and E12.5. Most of E10.5NML–/–embryos exhibited growth retardation and/or malformation with marked impairment of erythropoiesis. Consistent with a previous study, the m1A in 28S rRNA was dramatically reduced inNML–/–foetal liver (FL) cells. Because the previous study demonstrated p53-dependent apoptosis ofNML-knockdown cells, and because we observed upregulation of p21, one of the p53 target genes, inNML–/–FL cells, we tested whetherp53disruption cancelled theNML-deficient phenotypes. Contrary to our expectation, suppression of p53 did not rescue the lethality or impaired erythropoiesis ofNML–/–embryos, suggesting that p53-independent mechanisms underlie theNML-deficient phenotypes. These results clarify an essential role of NML during embryogenesis, particularly in erythropoiesis. We surmise that embryonic erythropoiesis is particularly sensitive to impaired protein synthesis, which is caused by the defective methylation of rRNA and consequent failure of ribosome formation.