CHD7 promotes neural progenitor differentiation in embryonic stem cells via altered chromatin accessibility and nascent gene expression.
CHD7 promotes neural progenitor differentiation in embryonic stem cells via altered chromatin accessibility and nascent gene expression.
复制标题
DOI：
10.1038/s41598-020-74537-4
复制
发表时间：
2020-10-15
影响因子：
4.6
通讯作者：
Martin DM
中科院分区：
文献类型：
--
作者：
Yao H;Hannum DF;Zhai Y;Hill SF;Albanus RD';Lou W;Skidmore JM;Sanchez G;Saiakhova A;Bielas SL;Scacheri P;Ljungman M;Parker SCJ;Martin DM
CHARGE综合征是一种罕见的多发性先天性异常疾病，由染色质重塑蛋白基因CHD 7（染色体结构域解旋酶DNA结合蛋白7）的单倍不足引起。大脑异常和智力残疾通常在CHARGE患者中观察到，并且在CHARGE患者来源的iPSC和条件性敲除小鼠大脑中神经元分化减少。然而，CHD 7在神经系统发育中的作用机制还不清楚。在这项研究中，我们询问CHD 7是否通过改变染色质可及性促进神经祖细胞中的基因转录。我们使用来自Chd 7突变小鼠胚泡的Chd 7空胚胎干细胞（ESC）作为工具来研究CHD 7在神经元和神经胶质分化中的作用。Chd 7的缺失显著降低神经元和神经胶质细胞的分化。Sholl分析表明，Chd 7的损失受损的神经元的复杂性和分化的神经元的轴突长度。全基因组研究表明，Chd 7的缺失导致神经特异性基因的染色质可及性（ATAC-seq）和差异新生表达（Bru-Seq）。这些结果表明，CHD 7在NPC向神经元的转变过程中优先改变关键基因的染色质可及性以促进分化。我们的研究结果为理解细胞谱系获得过程中CHD 7介导的染色质重塑的细胞阶段特异性作用奠定了基础。
CHARGE syndrome, a rare multiple congenital anomaly condition, is caused by haploinsufficiency of the chromatin remodeling protein gene CHD7 (Chromodomain helicase DNA binding protein 7). Brain abnormalities and intellectual disability are commonly observed in individuals with CHARGE, and neuronal differentiation is reduced in CHARGE patient-derived iPSCs and conditional knockout mouse brains. However, the mechanisms of CHD7 function in nervous system development are not well understood. In this study, we asked whether CHD7 promotes gene transcription in neural progenitor cells via changes in chromatin accessibility. We used Chd7 null embryonic stem cells (ESCs) derived from Chd7 mutant mouse blastocysts as a tool to investigate roles of CHD7 in neuronal and glial differentiation. Loss of Chd7 significantly reduced neuronal and glial differentiation. Sholl analysis showed that loss of Chd7 impaired neuronal complexity and neurite length in differentiated neurons. Genome-wide studies demonstrated that loss of Chd7 leads to modified chromatin accessibility (ATAC-seq) and differential nascent expression (Bru-Seq) of neural-specific genes. These results suggest that CHD7 acts preferentially to alter chromatin accessibility of key genes during the transition of NPCs to neurons to promote differentiation. Our results form a basis for understanding the cell stage-specific roles for CHD7-mediated chromatin remodeling during cell lineage acquisition.
登录
查看更多内容
影响因子：
64.8
作者：
Konermann S;Brigham MD;Trevino AE;Joung J;Abudayyeh OO;Barcena C;Hsu PD;Habib N;Gootenberg JS;Nishimasu H;Nureki O;Zhang F
通讯作者：
Zhang F
影响因子：
5.2
作者：
Esmailpour, Taraneh;Huang, Taosheng
通讯作者：
Huang, Taosheng
影响因子：
10.5
作者：
Chai M;Sanosaka T;Okuno H;Zhou Z;Koya I;Banno S;Andoh-Noda T;Tabata Y;Shimamura R;Hayashi T;Ebisawa M;Sasagawa Y;Nikaido I;Okano H;Kohyama J
通讯作者：
Kohyama J
影响因子：
3.5
作者：
Bosman, EA;Penn, AC;Steel, KP
通讯作者：
Steel, KP
影响因子：
23.9
作者：
Feng, Weijun;Khan, Muhammad Amir;Liu, Hai-Kun
通讯作者：
Liu, Hai-Kun