The endothelial-specific LINC00607 mediates endothelial angiogenic function

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 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.

Admixture Mapping of Peripheral Artery Disease in a Dominican Population Reveals a Novel Risk Locus on 2q35

“…The top tag SNP, rs78529201, falls within an intron of the lincRNA, LINC00607 . Bulk tissue gene expression results from the Genotype-Tissue Expression portal (GTEx Portal) show the tissue with the highest expression of LINC00607 are arteries (Sriram et al, 2022) and another recent study demonstrated it is highly enriched in endothelial cells (Boos et al, 2022). Previous work has shown a key role of LINC00607 in the control of cellular processes underlying inflammatory responses, angiogenesis, collagen catabolism and extracellular matrix organization in endothelial cells via its inactivation of PAI-1 , an inhibitor of plasminogen activators (Calandrelli et al, 2019; Sriram et al, 2022).…”

“…Fine-mapping at this locus implicated a tag SNP rs78529201 located within long intergenic non-coding RNA (lincRNA) LINC00607 . Existing literature highlights LINC00607 as a super enhancer in a gene expression network that is critical for regulation of normal endothelial cell function as well as dysfunction, suggesting a putative link of the 2q35 locus to PAD etiology (Calandrelli et al, 2019; Boos et al, 2022; Sriram et al, 2022).…”

Admixture mapping of peripheral artery disease in a Dominican population reveals a putative risk locus on 2q35

“…The top tag SNP, rs78529201, falls within an intron of the lincRNA, LINC00607. Bulk tissue gene expression results from the Genotype-Frontiers in Genetics frontiersin.org Tissue Expression portal (GTEx Portal, 2022) show the tissues with the highest expression of LINC00607 are arteries (Sriram et al, 2022), and another recent study demonstrated that it is highly enriched in endothelial cells (Boos et al, 2022). Previous work has shown a key role of LINC00607 in the control of cellular processes underlying inflammatory responses, angiogenesis, collagen catabolism, and Frontiers in Genetics frontiersin.org extracellular matrix organization in endothelial cells via its inactivation of PAI-1, an inhibitor of plasminogen activators (Calandrelli et al, 2019;Sriram et al, 2022).…”