LINC00607 is essential to maintain the endothelial phenotype through SWI/SNF chromatin remodeler BRG1

ABSTRACT: Long non-coding RNAs (lncRNAs) are regulatory RNAs, which by altering gene expression impact on the cellular phenotype and cardiovascular disease development. The pool of endothelial lncRNAs and their vascular function is largely undefined. Deep-endothelial RNA-Seq and FANTOM5 CAGE analysis revealed LINC00607 as a specifically enriched and highly expressed lncRNA 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 HUVEC also integrated less into newly formed vascular networks in an in vivo assay in SCID mice. Overexpression of LINC00607 in CRISPR knockout cells restored the normal function. RNA- and ATAC-Seq of the LINC00607 knockout revealed changes in transcription of endothelial gene sets particularly linked to the endothelial phenotype. This was most likely the consequence of a reduced chromatin accessibility of the ERG binding motif. Mechanistically, LINC00607 interacts 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 a highly expressed endothelial-specific lncRNA important for efficient endothelial gene transcription through sustaining ERG target gene transcription by interaction with the chromatin remodeler BRG1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE201824 | GEO | 2023/01/09

REPOSITORIES: GEO