Autism-associated chromatin remodeler CHD8 regulates erythroblast cytokinesis and fine-tunes the balance of Rho GTPase signaling.
Autism-associated chromatin remodeler CHD8 regulates erythroblast cytokinesis and fine-tunes the balance of Rho GTPase signaling.
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孤独症相关染色质重塑因子CHD8调节成红细胞胞质分裂并微调Rho GT3信号传导的平衡
DOI：
10.1016/j.celrep.2022.111072
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发表时间：
2022-07-12
期刊：
影响因子：
8.8
通讯作者：
Zheng, Yi
中科院分区：
文献类型：
--
作者：
Tu, Zhaowei;Fan, Cuiqing;Davis, Ashely K.;Hu, Mengwen;Wang, Chen;Dandamudi, Akhila;Seu, Katie G.;Kalfa, Theodosia A.;Lu, Q. Richard;Zheng, Yi
CHD 8是ATP依赖性染色质重塑因子，其单等位基因突变定义了自闭症谱系障碍（ASD）的亚型。先前的工作发现CHD 8是通过整合ATM-P53介导的造血干/祖细胞（HSPC）存活来维持造血所必需的。在这里，通过使用Chd 8 F/FMx 1-Cre与抑制Chd 8 −/− HSPCs凋亡的Trp 53 F/F小鼠模型相结合，我们将CHD 8确定为红系分化的重要调节因子。Chd 8 −/− P53−/−小鼠表现出严重贫血，符合先天性红细胞生成不良性贫血（CDA）表型。CHD 8的缺失导致正染性成红细胞数量急剧减少，双核和多核嗜碱性成红细胞增加，成红细胞胞质分裂失败。CHD 8直接与成红细胞中多个Rho GT3信号传导基因的基因体结合，CHD 8的缺失导致其表达失调，导致RhoA降低和Rac 1和Cdc 42活性增加。我们的研究表明，自闭症相关的CHD 8是必要的红细胞胞质分裂。Tu等报道，CHD 8是一种自闭症相关的染色质重塑剂，对红细胞分化至关重要。CHD 8的缺失导致Rho GT3信号传导不平衡和成红细胞胞质分裂缺陷，类似于先天性红细胞生成障碍性贫血。
CHD8 is an ATP-dependent chromatin-remodeling factor whose monoallelic mutation defines a subtype of autism spectrum disorders (ASDs). Previous work found that CHD8 is required for the maintenance of hematopoiesis by integrating ATM-P53-mediated survival of hematopoietic stem/progenitor cells (HSPCs). Here, by using Chd8F/FMx1-Cre combined with a Trp53F/F mouse model that suppresses apoptosis of Chd8−/− HSPCs, we identify CHD8 as an essential regulator of erythroid differentiation. Chd8−/− P53−/− mice exhibited severe anemia conforming to congenital dyserythropoietic anemia (CDA) phenotypes. Loss of CHD8 leads to drastically decreased numbers of orthochromatic erythroblasts and increased binucleated and multinucleated basophilic erythroblasts with a cytokinesis failure in erythroblasts. CHD8 binds directly to the gene bodies of multiple Rho GTPase signaling genes in erythroblasts, and loss of CHD8 results in their dysregulated expression, leading to decreased RhoA and increased Rac1 and Cdc42 activities. Our study shows that autism-associated CHD8 is essential for erythroblast cytokinesis. Tu et al. report that CHD8, an autism-related chromatin remodeler, is essential for erythroid differentiation. Loss of CHD8 leads to unbalanced Rho GTPase signaling and defective erythroblast cytokinesis, mimicking that of congenital dyserythropoietic anemia.
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影响因子：
20.3
作者：
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