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
  • Zebrafish*
  • Hemangioma, Cavernous, Central Nervous System*/genetics
  • Hemangioma, Cavernous, Central Nervous System*/metabolism
  • Hemangioma, Cavernous, Central Nervous System*/pathology
  • Endothelial Cells/metabolism
  • Animals
  • Zebrafish Proteins*/genetics
  • Zebrafish Proteins*/metabolism
  • Signal Transduction
  • Polycomb Repressive Complex 1*/genetics
  • Polycomb Repressive Complex 1*/metabolism
  • Humans
  • Epigenesis, Genetic*
  • Mice
  • Kruppel-Like Transcription Factors/genetics
  • Kruppel-Like Transcription Factors/metabolism
  • Disease Models, Animal
(all 17)
PubMed
39402138 Full text @ EMBO Mol. Med.
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
Figures
Figure Gallery (4 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
bns208
    		Small Deletion
    hu1667
      		Point Mutation
      ig1TgTransgenic Insertion
        m201
          		Point Mutation
          mu107TgTransgenic Insertion
            pbb42
              		Small Deletion
              pbb62
                		Small Deletion
                s843TgTransgenic Insertion
                  sa20083
                    		Point Mutation
                    sh317
                      		Small Deletion
                      1 - 10 of 13
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                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      cbx7aCRISPR1-cbx7aCRISPR
                      cbx7aCRISPR2-cbx7aCRISPR
                      cbx7aMO2-cbx7aMRPHLNO
                      tnnt2aMO1-tnnt2aMRPHLNO
                      wnt9bMO2-wnt9bMRPHLNO
                      1 - 5 of 5
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                      Fish
                      No data available
                      Antibodies
                      Orthology
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      CitrineEFGCitrine
                      EGFPEFGEGFP
                      GAL4FFEFGGAL4FF
                      mCherryEFGmCherry
                      1 - 4 of 4
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                      Mapping
                      No data available
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                      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.