Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations
Pham, Van-Cuong; Rödel, Claudia Jasmin; Valentino, Mariaelena; Malinverno, Matteo; Paolini, Alessio; Münch, Juliane; Pasquier, Candice; Onyeogaziri, Favour C; Lazovic, Bojana; Girard, Romuald; Koskimäki, Janne; Hußmann, Melina; Keith, Benjamin; Jachimowicz, Daniel; Kohl, Franziska; Hagelkruys, Astrid; Penninger, Josef M; Schulte-Merker, Stefan; Awad, Issam A; Hicks, Ryan; Magnusson, Peetra U; Faurobert, Eva; Pagani, Massimiliano; Abdelilah-Seyfried, Salim (2024-10-14)
Pham, Van-Cuong
Rödel, Claudia Jasmin
Valentino, Mariaelena
Malinverno, Matteo
Paolini, Alessio
Münch, Juliane
Pasquier, Candice
Onyeogaziri, Favour C
Lazovic, Bojana
Girard, Romuald
Koskimäki, Janne
Hußmann, Melina
Keith, Benjamin
Jachimowicz, Daniel
Kohl, Franziska
Hagelkruys, Astrid
Penninger, Josef M
Schulte-Merker, Stefan
Awad, Issam A
Hicks, Ryan
Magnusson, Peetra U
Faurobert, Eva
Pagani, Massimiliano
Abdelilah-Seyfried, Salim
Wiley-Blackwell
14.10.2024
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., … Abdelilah-Seyfried, S. (2024). Epigenetic regulation by polycomb repressive complex 1 promotes cerebral cavernous malformations. EMBO Molecular Medicine, 16(11), 2827–2855. https://doi.org/10.1038/s44321-024-00152-9
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https://creativecommons.org/licenses/by/4.0/
© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Creative Com- mons Public Domain Dedication waiver http://creativecommons.org/public-domain/zero/1.0/ applies to the data associated with this article, unless otherwise stated in a credit line to the data, but does not extend to the graphical or creative elements of illustrations, charts, or figures. This waiver removes legal barriers to the re-use and mining of research data. According to standard scholarly practice, it is recommended to provide appropriate citation and attribution whenever technically possible.
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Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202410166343
https://urn.fi/URN:NBN:fi:oulu-202410166343
Tiivistelmä
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.
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.
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