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. Synopsis: A novel therapeutic approach for the treatment of cerebral cavernous malformation (CCM) was established through targeting the polycomb repressive complex 1 protein CBX7. In CCM, brain endothelial cells exhibit increased epigenetic modifications due to activity of the polycomb repressive complex 1 protein CBX7. Changes to the epigenetic landscape in affected endothelial cells trigger a pathological gene expression that involves TEK, ANGPT1, WNT9, and endoMT genes. The activity of CBX7 is regulated by the transcriptional regulator KLF2 and blood flow. Genetic ablation or pharmacological inhibition of CBX7 in pre-clinical zebrafish, mouse, and human endothelial cell models suppresses cerebral cavernous malformation phenotypes. A novel therapeutic approach for the treatment of cerebral cavernous malformation (CCM) was established through targeting the polycomb repressive complex 1 protein CBX7. [ABSTRACT FROM AUTHOR]