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
{"title":"多聚酶抑制复合体 1 的表观遗传调控促进了脑海绵畸形。","authors":"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","doi":"10.1038/s44321-024-00152-9","DOIUrl":null,"url":null,"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.","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.0000,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations.\",\"authors\":\"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\",\"doi\":\"10.1038/s44321-024-00152-9\",\"DOIUrl\":null,\"url\":null,\"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. 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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.
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)