Background: Long non-coding RNAs (lncRNAs) can act as molecular switches in cellular differentiation, disease and in the reprogramming of cell states by altering gene expression. Endothelial lncRNAs and their vascular functions are only poorly understood. We identified LINC00607 as a highly expressed and endothelial-enriched lncRNA, whose function and the mode of action was investigated here.

Results: Deep RNA-Seq and FANTOM5 CAGE revealed that LINC00607 is among the highest expressed lncRNAs in endothelial cells. LINC00607 was induced in response to hypoxia, endothelial-to-mesenchymal transition and in atherosclerotic plaques. 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.

Conclusions: LINC00607 is a highly expressed endothelial-specific lncRNA important for vascular phenotype control. By interacting with the chromatin remodeler BRG1, LINC00607 maintains ERG target gene transcription.