Enhancer-associated LncRNA-ITGA2 promotes vascular smooth muscle remodeling by mediating ITGA2 promoter-enhancer interactions

ABSTRACT: In this study, multiomics profiling, including CUT&Tag, promoter capture Hi-C (PCHi-C), and microarray, identified LncRNA-ITGA2 as a novel elncRNA that was highly expressed in PDGF-induced proliferative human VSMCs. Notably, LncRNA-ITGA2 was significantly increased in both plasma and coronary atherosclerotic tissues of patients with coronary artery disease (CAD) compared with control subjects. Loss- and gain-of-function studies revealed that LncRNA-ITGA2 potently increased PDGF-induced VSMC proliferation and migration. Moreover, LncRNA-ITGA2 overexpression enhanced neointimal hyperplasia in vivo in a mouse carotid artery injury model, exhibiting its partial functional conservation. RNA-sequencing and CRISPR-Cas9 gene-editing technology revealed integrin α2 (ITGA2) as a downstream target of LncRNA-ITGA2 in VSMCs. Mechanistically, promoter-enhancer interactions were detected by PCHi-C at the ITGA2 locus after PDGF-BB treatment. Chromatin immunoprecipitation sequencing (ChIP-Seq) and chromatin isolation by RNA purification (ChIRP)-qPCR showed that LncRNA-ITGA2 directly bound to the Enhancer-ITGA2 and increased H3K27 acetylation in both the Enhancer-ITGA2 and Promoter-ITGA2. In addition, we demonstrated, by ChIRP-MS and RNA immunoprecipitation, that LncRNA-ITGA2 interacted with the DNA binding-protein NONO (non-pou domain containing octamer-binding protein), which also bound to the ITGA2 promoter, as verified by the ChIP-qPCR assay. Ultimately, the knockout cell lines of NONO, LncRNA-ITGA2, and its promoter confirmed the above regulatory mechanism.

ORGANISM(S): Homo sapiens

PROVIDER: GSE248192 | GEO | 2024/12/31

REPOSITORIES: GEO