PUBLICATION
Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations
- Authors
- Pham, V.C., Rödel, C.J., Valentino, M., Malinverno, M., Paolini, A., Münch, J., Pasquier, C., Onyeogaziri, F.C., Lazovic, B., Girard, R., Koskimäki, J., Hußmann, M., Keith, B., Jachimowicz, D., Kohl, F., Hagelkruys, A., Penninger, J.M., Schulte-Merker, S., Awad, I.A., Hicks, R., Magnusson, P.U., Faurobert, E., Pagani, M., Abdelilah-Seyfried, S.
- ID
- ZDB-PUB-241015-11
- Date
- 2024
- Source
- EMBO Molecular Medicine 16(11): 2827-2855 (Journal)
- Registered Authors
- Abdelilah-Seyfried, Salim, Schulte-Merker, Stefan
- Keywords
- CBX7, Cerebral Cavernous Malformation, KLF2, WNT9, endoMT
- Datasets
- GEO:GSE277234
- MeSH Terms
-
- Endothelial Cells/metabolism
- Zebrafish*
- Hemangioma, Cavernous, Central Nervous System*/genetics
- Hemangioma, Cavernous, Central Nervous System*/metabolism
- Hemangioma, Cavernous, Central Nervous System*/pathology
- Mice
- Disease Models, Animal
- Signal Transduction
- Epigenesis, Genetic*
- Kruppel-Like Transcription Factors/genetics
- Kruppel-Like Transcription Factors/metabolism
- Humans
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Animals
- Polycomb Repressive Complex 1*/genetics
- Polycomb Repressive Complex 1*/metabolism
- PubMed
- 39402138 Full text @ EMBO Mol. Med.
Citation
Pham, V.C., Rödel, C.J., Valentino, M., Malinverno, M., Paolini, A., Münch, J., Pasquier, C., Onyeogaziri, F.C., Lazovic, B., Girard, R., Koskimäki, J., Hußmann, M., Keith, B., Jachimowicz, D., Kohl, F., Hagelkruys, A., Penninger, J.M., Schulte-Merker, S., Awad, I.A., Hicks, R., Magnusson, P.U., Faurobert, E., Pagani, M., Abdelilah-Seyfried, S. (2024) Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations. EMBO Molecular Medicine. 16(11):2827-2855.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping