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Loss of the CCM proteins CCM1\/KRIT1, CCM2, or CCM3\/PDCD10 trigger a MAPK-Kr\u00fcppel-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.\n                    <jats:italic>CBX7<\/jats:italic>\n                    \/\n                    <jats:italic>cbx7a<\/jats:italic>\n                    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\n                    <jats:italic>ccm2<\/jats:italic>\n                    zebrafish, CCM2-deficient HUVECs, and in a pre-clinical murine\n                    <jats:italic>CCM3<\/jats:italic>\n                    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\n                    <jats:italic>TEK<\/jats:italic>\n                    ,\n                    <jats:italic>ANGPT1<\/jats:italic>\n                    ,\n                    <jats:italic>WNT9<\/jats:italic>\n                    , 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.\n                  <\/jats:p>","DOI":"10.1038\/s44321-024-00152-9","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T06:03:04Z","timestamp":1728885784000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4787-7013","authenticated-orcid":false,"given":"Van-Cuong","family":"Pham","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2384-1537","authenticated-orcid":false,"given":"Claudia 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