Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations.

Publisher: EMBO Press Country of Publication: Germany NLM ID: 101487380 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1757-4684 (Electronic) Linking ISSN: 17574676 NLM ISO Abbreviation: EMBO Mol Med Subsets: MEDLINE

Publication: 2024- : Heidelberg : EMBO Press
Original Publication: Chichester, West Sussex : Wiley-Blackwell

Zebrafish* ; Hemangioma, Cavernous, Central Nervous System*/genetics ; Hemangioma, Cavernous, Central Nervous System*/metabolism ; Hemangioma, Cavernous, Central Nervous System*/pathology ; Epigenesis, Genetic* ; Polycomb Repressive Complex 1*/metabolism ; Polycomb Repressive Complex 1*/genetics ; Zebrafish Proteins*/genetics ; Zebrafish Proteins*/metabolism; Animals ; Humans ; Mice ; Kruppel-Like Transcription Factors/metabolism ; Kruppel-Like Transcription Factors/genetics ; Endothelial Cells/metabolism ; Disease Models, Animal ; Signal Transduction

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.
Competing Interests: Disclosure and competing interests statement SA-S holds a European patent (EP4 154 876) related to this study.
(© 2024. The Author(s).)

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INST 336/114-1 FUGG Deutsche Forschungsgemeinschaft (DFG); P01 NS092521 United States NS NINDS NIH HHS; IG2019-ID 23826 AIRC; V.A.Cure EC | Horizon Europe | Excellent Science | HORIZON EUROPE Marie Sklodowska-Curie Actions (MSCA); 1238 GGP19202 Italy TI_ Telethon; CRC1348B08 Deutsche Forschungsgemeinschaft (DFG); P01NS092521 NIH/NINDS; SE2016/7-3,SE2016/10-1,SE2016/13-1,SFB958 Deutsche Forschungsgemeinschaft (DFG); 21CVD03 - ReVAMP Fondation Leducq (Leducq Foundation); PNRR M4C2-Investimento 1.4-CN00000041 - NextGenerationEU Ministero dell'Istruzione, dell'Università e della Ricerca award

Keywords: CBX7; Cerebral Cavernous Malformation; KLF2; WNT9; endoMT

EC 2.3.2.27 (Polycomb Repressive Complex 1)
0 (Zebrafish Proteins)
0 (Kruppel-Like Transcription Factors)
0 (KLF2 protein, human)
0 (Klf2a protein, zebrafish)

Date Created: 20241014 Date Completed: 20241111 Latest Revision: 20241114

20241114

PMC11555420

10.1038/s44321-024-00152-9

39402138