RNF213 loss of function reshapes vascular transcriptome and spliceosome leading to disrupted angiogenesis and aggravated vascular inflammatory responses
RNF213 loss of function reshapes vascular transcriptome and spliceosome leading to disrupted angiogenesis and aggravated vascular inflammatory responses
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DOI：
10.1177/0271678x221110679
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发表时间：
2022-06
影响因子：
6.3
通讯作者：
Liyin Zhang;Sherif Rashad;Yuan-da Zhou;Kuniyasu Niizuma;T. Tominaga
中科院分区：
文献类型：
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作者：
Liyin Zhang;Sherif Rashad;Yuan-da Zhou;Kuniyasu Niizuma;T. Tominaga
RNF 213基因突变是Moyamoya病的原因，Moyamoya病是一种罕见的脑血管闭塞性疾病。然而，RNF 213在血管系统中的功能及其功能丧失的影响尚未被理解。为了了解RNF 23的功能，我们在血管细胞中进行了基因敲低（KD），并进行了各种表型分析以及广泛的转录组和表位转录组分析。我们的数据显示，RNF 213 KD导致HUVEC中血管生成中断，部分原因是DNA复制和增殖途径下调。此外，在RNF 213 KD后，HUVEC细胞变得对LPS诱导的炎症敏感，导致细胞迁移延迟和巨噬细胞迁移增强。这在转录组水平上也很明显。有趣的是，RNF 213导致了mRNA剪接的广泛变化，这是以前没有报道过的。在血管平滑肌细胞（vSMC）中，RNF 213 KD导致细胞骨架组织、收缩性和vSMC功能相关通路的改变。最后，RNF 213 KD在共培养模型中破坏了内皮细胞与vSMC的通讯。总之，我们的结果表明RNF 213 KD使内皮细胞对炎症敏感，导致血管生成改变。我们的研究结果揭示了RNF 213突变和MMD的炎症/免疫诱导剂之间的重要联系，以及表转录组在MMD中未探索的作用。
RNF213 gene mutations are the cause behind Moyamoya disease, a rare cerebrovascular occlusive disease. However, the function of RNF213 in the vascular system and the impact of its loss of function are not yet comprehended. To understand RNF23 function, we performed gene knockdown (KD) in vascular cells and performed various phenotypical analysis as well as extensive transcriptome and epitranscriptome profiling. Our data revealed that RNF213 KD led to disrupted angiogenesis in HUVEC, in part due to downregulation of DNA replication and proliferation pathways. Furthermore, HUVEC cells became sensitive to LPS induced inflammation after RNF213 KD, leading to retarded cell migration and enhanced macrophage transmigration. This was evident at the level of transcriptome as well. Interestingly, RNF213 led to extensive changes in mRNA splicing that were not previously reported. In vascular smooth muscle cells (vSMCs), RNF213 KD led to alteration in cytoskeletal organization, contractility, and vSMCs function related pathways. Finally, RNF213 KD disrupted endothelial-to-vSMCs communication in co-culture models. Overall, our results indicate that RNF213 KD sensitizes endothelial cells to inflammation, leading to altered angiogenesis. Our results shed the light on the important links between RNF213 mutations and inflammatory/immune inducers of MMD and on the unexplored role of epitranscriptome in MMD.