Cerebral cavernous malformations (CCMs) are anomalies of the cerebral vasculature. Loss of the CCM proteins CCM1/KRIT1, CCM2, or CCM3/PDCD10 trigger a MAPK-Krüppel-like factor 2 (KLF2) signaling cascade, which induces a pathophysiological pattern of gene expression. The downstream target genes that are activated by KLF2 are mostly unknown. Here we show that Chromobox Protein Homolog 7 (CBX7), component of the Polycomb Repressive Complex 1, contributes to pathophysiological KLF2 signaling during zebrafish cardiovascular development. CBX7/cbx7a mRNA is strongly upregulated in lesions of CCM patients, and in human, mouse, and zebrafish CCM-deficient endothelial cells. The silencing or pharmacological inhibition of CBX7/Cbx7a suppresses pathological CCM phenotypes in ccm2 zebrafish, CCM2-deficient HUVECs, and in a pre-clinical murine CCM3 disease model. Whole-transcriptome datasets from zebrafish cardiovascular tissues and human endothelial cells reveal a role of CBX7/Cbx7a in the activation of KLF2 target genes including TEK, ANGPT1, WNT9, and endoMT-associated genes. Our findings uncover an intricate interplay in the regulation of Klf2-dependent biomechanical signaling by CBX7 in CCM. This work also provides insights for therapeutic strategies in the pathogenesis of CCM.

中文翻译：

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多梳抑制复合物 1 的表观遗传调控促进脑海绵状血管畸形。


脑海绵状血管畸形 （CCM） 是脑血管系统的异常。CCM 蛋白 CCM1/KRIT1、CCM2 或 CCM3/PDCD10 缺失会触发 MAPK-Krüppel 样因子 2 （KLF2） 信号级联反应，从而诱导基因表达的病理生理模式。被 KLF2 激活的下游靶基因大多是未知的。在这里，我们表明 Chromobox 蛋白同源物 7 （CBX7） 是多梳抑制复合物 1 的组成部分，有助于斑马鱼心血管发育过程中的病理生理学 KLF2 信号传导。CBX7/cbx7a mRNA 在 CCM 患者的病变以及人、小鼠和斑马鱼 CCM 缺陷的内皮细胞中强烈上调。CBX7/Cbx7a 的沉默或药理学抑制抑制 ccm2 斑马鱼、CCM2 缺陷型 HUVEC 和临床前小鼠 CCM3 疾病模型中的病理 CCM 表型。来自斑马鱼心血管组织和人内皮细胞的全转录组数据集揭示了 CBX7/Cbx7a 在 KLF2 靶基因（包括 TEK、ANGPT1、WNT9 和 endoMT 相关基因）激活中的作用。我们的研究结果揭示了 CCM 中 CBX7 对 Klf2 依赖性生物力学信号传导的调节中存在错综复杂的相互作用。这项工作还为 CCM 发病机制的治疗策略提供了见解。