Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations

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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Publication Details

Journal
EMBO Molecular Medicine
Published
2024-10-14
DOI
https://doi.org/10.1038/s44321-024-00152-9
Citations
8
Primary Topic
Vascular Malformations Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
2.95

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article

Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations

Alessio Paolini, Ryan Hicks, Mariaelena Valentino, Peetra U. Magnusson et al.
8 citations
EMBO Molecular Medicine
Vascular Malformations Diagnosis and Treatment
2.95
article

Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations

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

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.

EMBO Molecular MedicineVol. 16(11)
Uppsala University (SE), Institute of Molecular Biotechnology (AT), Centre National de la Recherche Scientifique (FR), Austrian Academy of Sciences (AT), Inserm (FR), University of Potsdam (DE), King's College London (GB), University of Milan (IT), Science for Life Laboratory (SE), Karolinska Institutet (SE), University of Chicago (US), AstraZeneca (Australia) (AU), IFOM (IT), King's College School (GB), Helmholtz Centre for Infection Research (DE), AstraZeneca (Japan) (JP), AstraZeneca (Sweden) (SE), Institut de Biosciences et Biotechnologies (FR), Neurological Surgery (US), Institut pour l'avancée des biosciences (FR), Organogenesis (United States) (US), Université Grenoble Alpes (FR), University of Oulu (FI)
Deutsche Forschungsgemeinschaft, Fondation Leducq, Association Nationale de la Recherche et de la Technologie, Associazione Italiana per la Ricerca sul Cancro, Akademiska Sjukhuset, Sigrid Juséliuksen Säätiö, Uppsala Universitet, National Institutes of Health, National Institute of Neurological Disorders and Stroke, HORIZON EUROPE Marie Sklodowska-Curie Actions
Openalex Percentile: Top 8%
Vascular Malformations Diagnosis and Treatment
2.95
DOIOpen Access PDFOpenAlex
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