CHD7 regulates otic lineage specification and hair cell differentiation in human inner ear organoids.
CHD7 regulates otic lineage specification and hair cell differentiation in human inner ear organoids.
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DOI：
10.1038/s41467-022-34759-8
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发表时间：
2022-11-17
影响因子：
16.6
通讯作者：
Hashino E
中科院分区：
文献类型：
--
作者：
Nie J;Ueda Y;Solivais AJ;Hashino E
CHD7的突变会导致电荷综合征，影响包括人类内耳在内的多个器官。我们使用人类多能干细胞衍生的有机化合物作为模型系统，研究CHD7突变如何影响内耳发育。我们发现CHD7或其染色质重塑活性的丢失导致毛细胞和支持细胞的完全缺失，这可以通过突变的生物前体中关键的听觉发育相关基因的失调来解释。对突变前体的进一步分析表明，CHD7可以通过不依赖染色质重塑的机制来调节新奇基因。毛细胞转录组图谱的结果显示，耳聋基因表达的中断是电荷相关性感音神经性听力损失的潜在潜在机制。值得注意的是，在嵌合有机体中共同分化CHD7基因敲除和野生型细胞，通过恢复原本严重失调的异常基因，部分挽救了突变的表型。综上所述，我们的结果表明CHD7在调节人类耳廓谱系特征和毛细胞分化方面起着关键作用。染色质重构体CHD7的突变会导致电荷综合征，影响包括内耳在内的几个器官的发育。在这里，作者用人类内耳类器官概括了这种疾病的发病机制，发现CHD7对于正确的耳系特征和毛细胞分化是必不可少的。
Mutations in CHD7 cause CHARGE syndrome, affecting multiple organs including the inner ear in humans. We investigate how CHD7 mutations affect inner ear development using human pluripotent stem cell-derived organoids as a model system. We find that loss of CHD7 or its chromatin remodeling activity leads to complete absence of hair cells and supporting cells, which can be explained by dysregulation of key otic development-associated genes in mutant otic progenitors. Further analysis of the mutant otic progenitors suggests that CHD7 can regulate otic genes through a chromatin remodeling-independent mechanism. Results from transcriptome profiling of hair cells reveal disruption of deafness gene expression as a potential underlying mechanism of CHARGE-associated sensorineural hearing loss. Notably, co-differentiating CHD7 knockout and wild-type cells in chimeric organoids partially rescues mutant phenotypes by restoring otherwise severely dysregulated otic genes. Taken together, our results suggest that CHD7 plays a critical role in regulating human otic lineage specification and hair cell differentiation. Mutations in the chromatin remodeler CHD7 cause CHARGE syndrome, affecting development of several organs including the inner ear. Here, the authors recapitulated pathogenesis of this disease with human inner ear organoids and found that CHD7 is indispensable for proper otic lineage specification and hair cell differentiation.
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影响因子：
14.8
作者：
通讯作者：
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影响因子：
16.6
作者：
Burns JC;Kelly MC;Hoa M;Morell RJ;Kelley MW
通讯作者：
Kelley MW
影响因子：
11.8
作者：
Ahmed, Mohi;Wong, Elaine Y. M.;Sun, Jianbo;Xu, Jinshu;Wang, Feng;Xu, Pin-Xian
通讯作者：
Xu, Pin-Xian
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：
64.5
作者：
Durruthy-Durruthy R;Gottlieb A;Hartman BH;Waldhaus J;Laske RD;Altman R;Heller S
通讯作者：
Heller S