Background: Long non-coding RNAs (lncRNAs) exerts numerous epigenetic mechanisms. Among them, they are discussed as molecular switches to control the cellular phenotype. However, in endothelial cells their role is not well understood. We set out to identify novel and functionally important endothelial-enriched lncRNAs and identified an important novel endothelial lncRNA.

Results: Deep RNA-seq and FANTOM5 search for endothelial-enriched lncRNAs yielded lncRNA LINC00607 among the top ten highest expressed lncRNA in endothelial cells. Silencing of LINC00607 with siRNAs, LNA-GapmeRs or LentiCRISPR-knockout in endothelial cells increased cellular proliferation and inhibited angiogenic sprouting in response to VEGF-A. LINC00607 was predominantly nuclear localized and highly upregulated in cells treated for endothelial to mesenchymal transition. Anti-sense oligo pulldown of LINC00607 followed by Mass spectrometry revealed the DNA-binding protein SSBP1 and the chromatin remodeler SMARCA3 as protein interaction partners. Chromatin remodeling is a dynamic process leading to modifications in chromatin architecture. Thereby it alters the access of to the transcriptional machinery to the chromatin. RNA-seq of CRISPR-mediated endothelial LINC00607 knockout cells revealed important phenotypic cues for LINC00607: Genes related to endothelial function including SERPINEs, Cadherins, PECAM1 and VWF, were strongly downregulated and genes involved in TGFß- and NOTCH-signaling pathways were upregulated upon loss of LINC00607. These data indicate that LINC00607 potentially recruits SSBP1 and SMARCA3 to its target sites to maintain endothelial function.

Conclusions: LINC00607 is a highly expressed endothelial specific lncRNA important for vascular phenotype control. The lncRNA appears to have a scaffolding function within the SMARCA3 chromatin-remodeling complex, facilitating and leading efficient key endothelial gene transcription to control the endothelial phenotype.