Wei Yufei, Wang Xinhuan, Ma Zhihua, Xiang Pan, Liu Gaoao, Yin Bin, Hou Lin, Shu Pengcheng, Liu Wei, Peng Xiaozhong
State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
Department of Molecular Biology and Biochemistry, Institute of Basic Medical Sciences, Medical Primate Research Center, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
iScience. 2023 Dec 9;27(2):108706. doi: 10.1016/j.isci.2023.108706. eCollection 2024 Feb 16.
Sirt6, a member of the class III histone deacetylases (HDACs), functions in the regulation of genomic stability, DNA repair, cancer, metabolism and aging. Sirt6 deficiency is lethal, and newborn SIRT6-null cynomolgus monkeys show unfinished brain development. After the generation of a cortex-specific Sirt6 conditional knockout mouse model, we investigated the specific deletion of Sirt6 in NPCs at E10.5. This study found that Sirt6 deficiency causes excessive proliferation of neural precursor cells (NPCs) and retards differentiation. The results suggest that endogenous Sirt6 in NPCs regulates histone acetylation and limits stemness-related genes, including Notch1, in order to participate in NPC fate determination. These findings help elucidate Sirt6's role in brain development and in NPC fate determination while providing data on species generality and differentiation.
沉默调节蛋白6（Sirt6）是Ⅲ类组蛋白去乙酰化酶（HDACs）的成员之一，在基因组稳定性、DNA修复、癌症、新陈代谢及衰老的调节过程中发挥作用。Sirt6基因缺陷是致命的，新生的SIRT6基因敲除食蟹猴表现出大脑发育不全。在构建了皮质特异性Sirt6条件性敲除小鼠模型后，我们研究了胚胎第10.5天神经前体细胞（NPCs）中Sirt6的特异性缺失情况。本研究发现，Sirt6基因缺陷会导致神经前体细胞过度增殖并阻碍其分化。结果表明，NPCs中的内源性Sirt6通过调节组蛋白乙酰化并限制包括Notch1在内的干性相关基因，从而参与NPCs的命运决定。这些发现有助于阐明Sirt6在大脑发育及NPCs命运决定中的作用，同时提供有关物种普遍性和分化的数据。
