NOGOB receptor deficiency increases cerebrovascular permeability and hemorrhage via impairing histone acetylation-mediated CCM1/2 expression.
NOGOB receptor deficiency increases cerebrovascular permeability and hemorrhage via impairing histone acetylation-mediated CCM1/2 expression.
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DOI：
10.1172/jci151382
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发表时间：
2022-05-02
影响因子：
15.9
通讯作者：
Miao, Qing Robert
中科院分区：
文献类型：
--
作者：
Fang, Zhi;Sun, Xiaoran;Wang, Xiang;Ma, Ji;Palaia, Thomas;Rana, Ujala;Miao, Benjamin;Ragolia, Louis;Hu, Wenquan;Miao, Qing Robert
脑海绵状血管畸形（CCM）基因的功能丧失导致大多数CCM病变以脑内扩大的渗漏性血管病变为特征。虽然我们以前表明，NOGOB受体（NGBR）敲除内皮细胞（EC）的结果在小鼠胚胎脑血管病变，NGBR调节CCM 1/2表达的分子机制尚未阐明。在这里，我们表明，在出生后和成人阶段的内皮细胞中Ngbr的遗传耗竭导致CCM 1/2表达缺陷和脑血管病变，如血管扩大，血脑屏障通透性过高，脑出血。为了揭示分子机制，我们使用RNA测序分析来检查转录组的变化。令人惊讶的是，我们发现乙酰转移酶HBO 1和组蛋白乙酰化在NGBR缺陷的EC中下调。机制研究阐明，NGBR是通过HBO 1介导的组蛋白乙酰化维持EC中CCM 1/2表达所必需的。ChIP-qPCR数据进一步证明NGBR的缺失损害了HBO 1与CCM 1和CCM 2基因启动子上乙酰化组蛋白H4 K5和H4 K12的结合。我们的研究结果对CCM 1和CCM 2的表观遗传调控是由NGBR和HBO 1介导的组蛋白H4乙酰化调节的，这为研究散发性CCM的发病机制提供了一个视角。
The loss function of cerebral cavernous malformation (CCM) genes leads to most CCM lesions characterized by enlarged leaking vascular lesions in the brain. Although we previously showed that NOGOB receptor (NGBR) knockout in endothelial cells (ECs) results in cerebrovascular lesions in the mouse embryo, the molecular mechanism by which NGBR regulates CCM1/2 expression has not been elucidated. Here, we show that genetic depletion of Ngbr in ECs at both postnatal and adult stages results in CCM1/2 expression deficiency and cerebrovascular lesions such as enlarged vessels, blood-brain-barrier hyperpermeability, and cerebral hemorrhage. To reveal the molecular mechanism, we used RNA-sequencing analysis to examine changes in the transcriptome. Surprisingly, we found that the acetyltransferase HBO1 and histone acetylation were downregulated in NGBR-deficient ECs. The mechanistic studies elucidated that NGBR is required for maintaining the expression of CCM1/2 in ECs via HBO1-mediated histone acetylation. ChIP-qPCR data further demonstrated that loss of NGBR impairs the binding of HBO1 and acetylated histone H4K5 and H4K12 on the promotor of the CCM1 and CCM2 genes. Our findings on epigenetic regulation of CCM1 and CCM2 that is modulated by NGBR and HBO1-mediated histone H4 acetylation provide a perspective on the pathogenesis of sporadic CCMs.