Vascular Regulation by Super Enhancer-Derived LINC00607

Abstract

Vascular endothelial cells (ECs) play a pivotal role in whole body homeostasis. Recent advances have revealed enhancer-associated long non-coding RNAs (lncRNAs) as essential regulators in EC function. We investigated LINC00607, a super enhancer-derived lncRNA (SE-lncRNA) in human arteries with an emphasis on ECs. Based on public databases and our single cell RNA-sequencing (scRNA-seq) data from human arteries collected from healthy and diabetic donors, we found that LINC00607 is abundantly expressed in the arteries and its level is increased in diabetic humans. Using RNA-sequencing, we characterized the transcriptomes regulated by LINC00607 in ECs and vascular smooth muscle cells (VSMCs) and in basal and diabetic conditions in ECs. Furthermore, through transcriptomic and promoter analysis, we identified c-Myc as an upstream transcription factor of LINC00607. Finally, using scRNA-seq, we demonstrated that modified antisense oligonucleotide inhibitor of LINC00607 can reverse dysfunctional changes induced by high glucose and TNFα in ECs. Collectively, our study demonstrates a multi-pronged approach to characterize LINC00607 in vascular cells and its gene regulatory networks in ECs and VSMCs. Our findings provide new insights into the regulation and function of SE-derived lncRNAs in both vascular homeostasis and dysfunction in a cell-type and context-dependent manner, which could have a significant impact on our understanding of epigenetic regulation implicated in cardiovascular health and diseases like diabetes.

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).…”

“…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). To assess the impact of harboring a risk allele on PAD risk, we showed that Dominican individuals who are heterozygous for SNP rs78529201 show a 37.2% risk of the disease compared to 13.3% of non-carriers (OR=3.88, CI 95% 2.06-7.31, P <1.95×10 -5 ).…”

“…LINC00607 knockout reduced SERPINE1 expression along with numerous other genes including FN1, TRIO and COL4 via a super enhancer network, promoting endothelial cell dysfunction (Calandrelli et al, 2019). LINC00607 is also implicated as a vital epigenetic regulator in arterial tissue and potential target for CVD therapies (Sriram et al, 2022). Taken together, this supports a role for LINC00607 as a gene expression regulator of key genes related to extracellular matrix organization, inflammation, angiogenesis and endotheliopathy, suggesting a putative link of the 2q35 locus to PAD etiology.…”

“…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

“…LINC00607 knockout reduced SERPINE1 expression along with numerous other genes including FN1 , TRIO , and COL4 via a super-enhancer network, promoting endothelial cell dysfunction ( Calandrelli et al, 2019 ). LINC00607 is also implicated as a vital epigenetic regulator in arterial tissue and a potential target for CVD therapies ( Sriram et al, 2022 ). Taken together, this supports a role for LINC00607 as a gene expression regulator of key genes related to extracellular matrix organization, inflammation, angiogenesis, and endotheliopathy, suggesting a putative link of the 2q35 locus to PAD etiology.…”