SIRT6 deficiency results in developmental retardation cynomolgus monkeys
SIRT6 deficiency results in developmental retardation cynomolgus monkeys
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SIRT6 缺陷导致食蟹猴发育迟缓
DOI：
10.1038/s41586-018-0437-z
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发表时间：
2018-08-30
期刊：
影响因子：
64.8
通讯作者：
Hu, Baoyang
中科院分区：
文献类型：
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作者：
Zhang, Weiqi;Wan, Haifeng;Hu, Baoyang
SIRT6在啮齿类动物中是一种长寿蛋白（1,2）。然而，它在灵长类动物中的生物学功能在很大程度上仍然未知。在这里，我们使用基于crispr - cas9的方法生成sirt6缺失的食蟹猴（Macaca fascicularis）模型。缺乏sirt6的猴子在出生数小时后死亡，并表现出严重的产前发育迟缓。SIRT6缺失通过转录激活长链非编码RNA H19（一种发育抑制因子）来延迟神经元分化，我们能够在人类神经祖细胞分化系统中概括这一过程。SIRT6缺陷导致H19印迹控制区组蛋白超乙酰化，CTCF募集和H19上调。我们的研究结果表明SIRT6参与调节非人灵长类动物的发育，并可能为人类围产期致死性综合征提供机制见解。
SIRT6 acts as a longevity protein in rodents(1,2). However, its biological function in primates remains largely unknown. Here we generate a SIRT6-null cynomolgus monkey (Macaca fascicularis) model using a CRISPR-Cas9-based approach. SIRT6-deficient monkeys die hours after birth and exhibit severe prenatal developmental retardation. SIRT6 loss delays neuronal differentiation by transcriptionally activating the long non-coding RNA H19 (a developmental repressor), and we were able to recapitulate this process in a human neural progenitor cell differentiation system. SIRT6 deficiency results in histone hyperacetylation at the imprinting control region of H19, CTCF recruitment and upregulation of H19. Our results suggest that SIRT6 is involved in regulating development in nonhuman primates, and may provide mechanistic insight into human perinatal lethality syndrome.