Histone Deacetylase 3 Governs Perinatal Cerebral Development via Neural Stem and Progenitor Cells
Histone Deacetylase 3 Governs Perinatal Cerebral Development via Neural Stem and Progenitor Cells
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组蛋白去乙酰化酶3通过神经干细胞和祖细胞调控围产期脑发育
DOI：
10.1016/j.isci.2019.09.015
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发表时间：
2019-10-25
期刊：
影响因子：
5.8
通讯作者：
Yang, Xiang-Jiao
中科院分区：
文献类型：
--
作者：
Li, Lin;Jin, Jianliang;Yang, Xiang-Jiao
我们报告大脑特异性组蛋白去乙酰化酶3（HDAC 3）基因的失活会导致新皮层、海马和胼胝体显著的发育缺陷;断奶后的致死率;以及异常行为，包括多动和焦虑。这些缺陷是由于胚胎神经干细胞和祖细胞（NSPCs）的快速丧失。在突变的大脑中，过早的神经发生和异常的神经元迁移改变了NSPC的稳态。突变的大脑皮层也显示出增强的DNA损伤反应、细胞凋亡和组蛋白过度乙酰化。此外，突变的NSPCs在体外形成神经球时受损，用HDAC 3特异性抑制剂RGFP 966治疗可消除神经球的形成。新生儿大脑皮质和培养的神经球的转录组学分析支持HDAC 3通过与不同转录因子（包括NFIB）相互作用来调节转录程序。这些发现确立HDAC 3作为小鼠大脑和NSPCs围产期发育的关键的主要脱乙酰酶，从而表明这种酶表观遗传调节剂与人类大脑和智力发育的直接联系。
We report that cerebrum-specific inactivation of the histone deacetylase 3 (HDAC3) gene causes striking developmental defects in the neocortex, hippocampus, and corpus callosum; post-weaning lethality; and abnormal behaviors, including hyperactivity and anxiety. The defects are due to rapid loss of embryonic neural stem and progenitor cells (NSPCs). Premature neurogenesis and abnormal neuronal migration in the mutant brain alter NSPC homeostasis. Mutant cerebral cortices also display augmented DNA damage responses, apoptosis, and histone hyperacetylation. Moreover, mutant NSPCs are impaired in forming neurospheres in vitro, and treatment with theHDAC3-specific inhibitor RGFP966 abolishes neurosphere formation. Transcriptomic analyses of neonatal cerebral cortices and cultured neurospheres support that HDAC3 regulates transcriptional programs through interaction with different transcription factors, including NFIB. These findings establish HDAC3 as a major deacetylase critical for perinatal development of the mouse cerebrum and NSPCs, thereby suggesting a direct link of this enzymatic epigenetic regulator to human cerebral and intellectual development.