Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations.

IF 9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EMBO Molecular Medicine Pub Date : 2024-10-14 DOI:10.1038/s44321-024-00152-9

Van-Cuong Pham,Claudia Jasmin Rödel,Mariaelena Valentino,Matteo Malinverno,Alessio Paolini,Juliane Münch,Candice Pasquier,Favour C Onyeogaziri,Bojana Lazovic,Romuald Girard,Janne Koskimäki,Melina Hußmann,Benjamin Keith,Daniel Jachimowicz,Franziska Kohl,Astrid Hagelkruys,Josef M Penninger,Stefan Schulte-Merker,Issam A Awad,Ryan Hicks,Peetra U Magnusson,Eva Faurobert,Massimiliano Pagani,Salim Abdelilah-Seyfried

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引用次数: 0

Abstract

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.

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多聚酶抑制复合体 1 的表观遗传调控促进了脑海绵畸形。

脑海绵畸形（CCMs）是一种脑血管畸形。CCM蛋白CCM1/KRIT1、CCM2或CCM3/PDCD10的缺失会触发MAPK-Krüppel样因子2（KLF2）信号级联，从而诱导病理生理模式的基因表达。KLF2激活的下游靶基因大多不为人知。在这里，我们发现多聚核抑制复合体 1 的成分 Chromobox Protein Homolog 7（CBX7）在斑马鱼心血管发育过程中有助于病理生理 KLF2 信号转导。CBX7/cbx7a mRNA在CCM患者的病变部位以及人、小鼠和斑马鱼CCM缺陷内皮细胞中强烈上调。沉默或药物抑制 CBX7/Cbx7a 可抑制 ccm2 斑马鱼、CCM2 缺失的 HUVEC 以及临床前小鼠 CCM3 疾病模型中的病理 CCM 表型。来自斑马鱼心血管组织和人类内皮细胞的全转录组数据集揭示了 CBX7/Cbx7a 在激活 KLF2 靶基因（包括 TEK、ANGPT1、WNT9 和 endoMT 相关基因）中的作用。我们的研究结果揭示了 CBX7 在 CCM 中调控 Klf2 依赖性生物力学信号转导过程中错综复杂的相互作用。这项研究还为 CCM 发病机制的治疗策略提供了启示。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EMBO Molecular Medicine 医学-医学：研究与实验

CiteScore

17.70

自引率

0.90%

发文量

105

审稿时长

4-8 weeks

期刊介绍： EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)