The endothelial-enriched lncRNA LINC00607 mediates angiogenic function

F. Boos, J.A. Oo, T. Warwick, S. Gunther, J.I. Ponce, M. Lopez, D. Rafii, G. Buchmann, M.D. Pham, Z.S. Msheik, T.F. Li, S. Seredinski, S. Haydar, S. Kashefiolasl, K.H. Plate, R. Behr, M. Mietsch, J. Krishnan, S.S. Pullamsetti, S.I. BibliR. Hinkel, A.H. Baker, R.A. Boon, M.H. Schulz, I. Wittig, F.J. Miller, R.P. Brandes*, M.S. Leisegang*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Long non-coding RNAs (lncRNAs) can act as regulatory RNAs which, by altering the expression of target genes, impact on the cellular phenotype and cardiovascular disease development. Endothelial lncRNAs and their vascular functions are largely undefined. Deep RNA-Seq and FANTOM5 CAGE analysis revealed the lncRNA LINC00607 to be highly enriched in human endothelial cells. LINC00607 was induced in response to hypoxia, arteriosclerosis regression in non-human primates, post-atherosclerotic cultured endothelial cells from patients and also in response to propranolol used to induce regression of human arteriovenous malformations. siRNA knockdown or CRISPR/Cas9 knockout of LINC00607 attenuated VEGF-A-induced angiogenic sprouting. LINC00607 knockout in endothelial cells also integrated less into newly formed vascular networks in an in vivo assay in SCID mice. Overexpression of LINC00607 in CRISPR knockout cells restored normal endothelial function. RNA- and ATAC-Seq after LINC00607 knockout revealed changes in the transcription of endothelial gene sets linked to the endothelial phenotype and in chromatin accessibility around ERG-binding sites. Mechanistically, LINC00607 interacted with the SWI/SNF chromatin remodeling protein BRG1. CRISPR/Cas9-mediated knockout of BRG1 in HUVEC followed by CUT&RUN revealed that BRG1 is required to secure a stable chromatin state, mainly on ERG-binding sites. In conclusion, LINC00607 is an endothelial-enriched lncRNA that maintains ERG target gene transcription by interacting with the chromatin remodeler BRG1 to ultimately mediate angiogenesis.
Original languageEnglish
Article number5
Number of pages21
JournalBasic Research in Cardiology
Volume118
Issue number1
DOIs
Publication statusPublished - 26 Jan 2023

Keywords

  • Long non-coding RNA
  • BRG1
  • Endothelial cell
  • Gene regulation
  • ERG
  • Hypoxia
  • MESENCHYMAL TRANSITION
  • CHROMATIN
  • PHOSPHORYLATION
  • MOUSE
  • CELLS
  • DNA

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