在Cynomolgus子中,SIRT6缺乏导致发育迟缓
Weiqi Zhang1,2,3,4, Haifeng Wan2,3,4, Guihai Feng2,3,4
1National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Nature
|August 24, 2018
概括
SIRT6对灵长类动物的发育至关重要. 通过H19激活来破坏神经元分化,导致子中SIRT6的损失导致严重的产前缺陷和早期死亡,从而为人类发育障碍提供了洞察力.
科学领域:
- 遗传学和发育生物学
- 灵长类模型
- 表观遗传学
背景情况:
- 在动物中,SIRT6被认为是一种长寿蛋白.
- 在灵长类动物的发育中,SIRT6的特定作用在很大程度上是未知的.
- 了解灵长类动物中的SIRT6功能对于比较生物学和人类健康至关重要.
研究的目的:
- 研究灵长类动物SIRT6的生物功能.
- 为了生成和表征SIRT6零子模型.
- 阐明SIRT6在发育中的作用的分子机制.
主要方法:
- 在CRISPR-Cas9基因编辑中,
- 对缺少SIRT6的子产前发育和生存率的分析.
- 使用人类神经前体细胞进行体外研究,以检查神经分化和H19调节.
主要成果:
- 缺少SIRT6的子出现严重的产前发育迟缓,并在出生后不久死亡.
- 通过长非编码RNA H19 的转录激活,SIRT6 损失导致神经元分化延迟.
- 缺少SIRT6会导致H19印记对照区域的素过化,从而增加H19的表达.
结论:
- 在非人类灵长类动物的产前发育中,SIRT6发挥着关键作用.
- 这种机制涉及SIRT6对H19的调节,H19是关键的发育抑制剂.
- 这些发现为人类周围死亡综合征提供了潜在的机械洞察力.
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