m6A调节血造干细胞和原生细胞的特异性
Chunxia Zhang1,2, Yusheng Chen2,3, Baofa Sun3
1State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Nature
|September 5, 2017
概括
N6-甲基氨酸 (m6A) RNA 修饰对于脊椎动物的胚胎生成至关重要,在内皮转化为血造细胞的过程中决定细胞命运,以确定早期的血造干细胞/原始细胞 (HSPC). 通过影响Notch信号,m6A的损失阻断了HSPC的产生.
科学领域:
- 表观遗传学和RNA生物学
- 发育生物学
- 血液形成
背景情况:
- N6-甲基氨酸 (m6A) 是真核生物中最常见的mRNA修饰,但其在脊椎动物胚胎发生中的作用在很大程度上是未知的.
- 高吞吐量测序技术已经提高了对m6A功能的理解.
- 细胞内皮转化为造血细胞 (EHT) 是产生第一个造血细胞干细胞/原始细胞 (HSPC) 的关键.
研究的目的:
- 研究m6A修饰在脊椎动物胚胎生成中的功能,特别是在EHT期间.
- 阐明m6A调节早期HSPC规范的分子机制.
主要方法:
- 在斑马鱼胚胎中利用m6A特异性甲基化RNA免疫沉与高通量测序 (MeRIP-seq) 和m6A个人核酸分辨率交叉链接和免疫沉.
- 产生的斑马鱼胚胎缺乏m6A,以评估降低m6A水平的影响.
- 在小鼠模型中进行基因破坏实验.
主要成果:
- 斑马鱼m6A甲基组的特征保存,在停止和RRACH图案附近的峰值.
- 已经证明,Mettl3缺乏会显著降低m6A水平,并阻止斑马鱼出现HSPC.
- 鉴定了mettil3缺陷胚胎中YTHDF2中介的notch1a和rhoca mRNA衰变导致持续的Notch信号,抑制ETH和HSPC生成.
- 在Mettl3- knockdown小鼠中观察到类似的表型.
结论:
- 在EHT期间确定细胞命运和在脊椎动物胚胎发生过程中确定早期的HSPC,m6A修饰是必不可少的.
- 在EHT过程中,mttl3- m6A途径通过控制mRNA衰变和Notch信号来调节HSPC的产生.
- 这些发现突显了m6A在脊椎动物发育过程中的血液形成调节中的保留和关键作用.
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