The autism-related protein CHD8 contributes to the stemness and differentiation of mouse hematopoietic stem cells
The autism-related protein CHD8 contributes to the stemness and differentiation of mouse hematopoietic stem cells
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DOI：
10.1016/j.celrep.2021.108688
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发表时间：
2021-02-02
期刊：
影响因子：
8.8
通讯作者：
Nakayama, Keiichi, I
中科院分区：
文献类型：
--
作者：
Nita, Akihiro;Muto, Yoshiharu;Nakayama, Keiichi, I
染色体结构域解旋酶DNA结合蛋白8（Chromodomain helicase DNA binding protein 8，CHD 8）是一种ATP依赖的染色质重塑因子，由自闭症谱系障碍患者中最常发生突变的基因编码。CHD 8不仅在神经组织中表达，而且在许多其他器官中也表达;然而，其功能在很大程度上是未知的。在这里，我们发现CHD 8在造血干细胞（HSC）中高度表达并维持造血干细胞的干细胞性。特异性地在小鼠骨髓中有条件地缺失Chd 8诱导与p53靶基因表达上调相关的HSC中的细胞周期停滞、凋亡和分化阻滞。集落形成试验和骨髓移植表明，CHD 8缺陷也会损害HSC的干性。此外，p53的额外消融挽救了受损的干细胞功能和CHD 8缺陷型HSC的分化阻滞。因此，我们的研究结果表明，CHD 8-p53轴在调控HSC的干细胞性和分化中起着关键作用。
Chromodomain helicase DNA-binding protein 8 (CHD8) is an ATP-dependent chromatin-remodeling factor that is encoded by the most frequently mutated gene in individuals with autism spectrum disorder. CHD8 is expressed not only in neural tissues but also in many other organs; however, its functions are largely unknown. Here, we show that CHD8 is highly expressed in and maintains the stemness of hematopoietic stem cells (HSCs). Conditional deletion of Chd8 specifically in mouse bone marrow induces cell cycle arrest, apoptosis, and a differentiation block in HSCs in association with upregulation of the expression of p53 target genes. A colony formation assay and bone marrow transplantation reveal that CHD8 deficiency also compromises the stemness of HSCs. Furthermore, additional ablation of p53 rescues the impaired stem cell function and differentiation block of CHD8-deficient HSCs. Our results thus suggest that the CHD8-p53 axis plays a key role in regulation of the stemness and differentiation of HSCs.