Defects of cohesin loader lead to bone dysplasia associated with transcriptional disturbance
Defects of cohesin loader lead to bone dysplasia associated with transcriptional disturbance
复制标题
粘连蛋白装载机的缺陷导致与转录紊乱相关的骨发育不良
DOI：
10.1002/jcp.30491
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发表时间：
2021-06-25
影响因子：
5.6
通讯作者：
Xu，Baoshan
中科院分区：
文献类型：
--
作者：
Gu，Weihuai;Wang，Lihong;Xu，Baoshan
Cohesin loader nipped B-like protein（Nipbl）因其在发育和癌症中的重要作用而日益受到重视。科尔内利亚德兰格综合征（CdLS）是一种以多器官畸形为特征的常染色体显性遗传病，主要由Nipbl基因杂合突变引起。然而，Nipbl在骨骼发育中的调节作用和潜在机制在很大程度上仍然难以捉摸。在这项研究中，我们构建了Nipbl-a Cas9-knockout（KO）斑马鱼，其表现出严重的整体生长和骨骼发育迟缓。缺乏Nipbl显著损害细胞生长和存活，以及哺乳动物成骨细胞前体的成骨分化。此外，Nipbl缺失会损害细胞周期进程，并导致DNA损伤累积和细胞衰老。此外，核仁原纤维蛋白表达，整体rRNA生物合成和蛋白质翻译在Nippl耗尽的成骨细胞前体中存在缺陷。有趣的是，一种整合的应激反应抑制剂（ISRIB）部分挽救了Nippl耗竭诱导的增殖和凋亡、骨生成和核仁功能的细胞缺陷。同时，我们结合Nippl ChIP-Seq对人神经嵴细胞和小鼠胚胎成纤维细胞进行了Nippl缺陷的转录组分析。我们发现Nippl缺陷导致了数千个差异表达的基因，包括一些在骨和软骨发育中的重要基因。总之，Nipbl缺乏通过损害成骨细胞前体细胞增殖和存活以及成骨分化，以及干扰一些成骨调控基因的表达，损害骨骼发育。我们的研究阐明了Nipbl在骨骼发育中起着关键作用，并支持ISRIB治疗可能提供早期干预策略以减轻CdLS的骨发育不良。
Cohesin loader nipped‐B‐like protein (Nipbl) is increasingly recognized for its important role in development and cancer. Cornelia de Lange Syndrome (CdLS), mostly caused by heterozygous mutations of Nipbl, is an autosomal dominant disease characterized by multiorgan malformations. However, the regulatory role and underlying mechanism of Nipbl in skeletal development remain largely elusive. In this study, we constructed a Nipbl‐a Cas9‐knockout (KO) zebrafish, which displayed severe retardation of global growth and skeletal development. Deficiency of Nipbl remarkably compromised cell growth and survival, and osteogenic differentiation of mammalian osteoblast precursors. Furthermore, Nipbl depletion impaired the cell cycle process, and caused DNA damage accumulation and cellular senescence. In addition, nucleolar fibrillarin expression, global rRNA biogenesis, and protein translation were defective in the Nipbl‐depleted osteoblast precursors. Interestingly, an integrated stress response inhibitor (ISRIB), partially rescued Nipbl depletion‐induced cellular defects in proliferation and apoptosis, osteogenesis, and nucleolar function. Simultaneously, we performed transcriptome analysis of Nipbl deficiency on human neural crest cells and mouse embryonic fibroblasts in combination with Nipbl ChIP‐Seq. We found that Nipbl deficiency caused thousands of differentially expressed genes including some important genes in bone and cartilage development. In conclusion, Nipbl deficiency compromised skeleton development through impairing osteoblast precursor cell proliferation and survival, and osteogenic differentiation, and also disturbing the expression of some osteogenesis‐regulatory genes. Our study elucidated that Nipbl played a pivotal role in skeleton development, and supported the fact that treatment of ISRIB may provide an early intervention strategy to alleviate the bone dysplasia of CdLS.