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SMAD2/3互动组显示TGFβ控制了多能性的mRNA甲基化
Alessandro Bertero1, Stephanie Brown1, Pedro Madrigal1,2
1Wellcome Trust-MRC Cambridge Stem Cell Institute, Anne McLaren Laboratory and Department of Surgery, University of Cambridge, Cambridge CB2 0SZ, UK.
Nature
|March 1, 2018
概括
转化生长因子β (TGFβ) 信号通过SMAD2/3蛋白调节细胞命运. 这项研究显示SMAD2/3与m6A甲基转移酶复合体相互作用,影响RNA稳定性和细胞分化.
科学领域:
- 细胞生物学
- 分子生物学
- 发育生物学
背景情况:
- 转化生长因子β (TGFβ) 途径对于胚胎发育,组织平衡和疾病至关重要.
- SMAD2和SMAD3 (SMAD2/3) 是TGFβ信号传递中介的关键细胞内效应体.
- 了解SMAD2/3相互作用者对于理解细胞生物学和疾病机制至关重要.
研究的目的:
- 在人类多能干细胞中阐明SMAD2/3的相互作用.
- 识别涉及转录调节之外的SMAD2/3的新分子过程.
- 发现SMAD2/3与RNA甲基化之间的功能联系.
主要方法:
- 在人类多能干细胞中测定SMAD2/3相互作用的蛋白质分析.
- 研究SMAD2/3与METTL3-METTL14-WTAPm6A甲基转移酶复合体之间的相互作用的生物化学测试.
- 通过RNA免疫沉,然后进行测序 (RIP-Seq) 来识别目标转录.
主要成果:
- 它与METTL3-METTL14-WTAP复合物相互作用,该复合物催化N6-甲基氨酸 (m6A) 的RNA修饰.
- 促进m6A甲基转移酶复合体与特定RNA转录物的结合.
- 这种相互作用会破坏SMAD2/3目标基因的稳定,包括NANOG,在分化过程中便于及时脱离多能性.
结论:
- 不仅通过转录来调节基因表达,还通过影响RNA表转录组来调节.
- 通过表体转录学调节,已发现的机制将细胞外TGFβ信号与细胞快速反应联系起来.
- 这一途径对了解细胞命运决策,干细胞生物学和癌症等疾病有重要意义.
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