SCAR-6 elncRNA locus epigenetically regulates PROZ and modulates coagulation and vascular function

In this study, we characterize the lncRNA locus known as Syntenic Cardiovascular Conserved Region-Associated lncRNA-6 (scar-6) and functionally validate its role in coagulation and cardiovascular function. Precise deletion of the scar-6 locus in zebrafish (scar-6gib007Δ12/Δ12) results in cranial hemorrhage and vascular permeability. Both overexpression, knockout and rescue of scar-6 lncRNA modulates hemostasis in zebrafish. Molecular investigation reveals that the scar-6 RNA acts as an enhancer lncRNA (elncRNA), and controls the expression of prozb, an inhibitor of factor Xa, through the enhancer element on its locus. The scar-6 locus suppresses loop formation between prozb and scar-6 sequences, facilitated by the methylation of CpG islands via the prdm14-PRC2 complex that is stabilized by the scar-6 elncRNA transcript. This complex is disrupted in scar-6gib007Δ12/Δ12 zebrafish. Furthermore, activation of the PAR2 receptor in scar-6gib007Δ12/Δ12 zebrafish triggers NF-ⲕB-mediated endothelial cell activation, leading to vascular dysfunction and hemorrhage. We present evidence that the scar-6 locus plays a role in regulating the expression of the coagulation cascade gene prozb and maintains vascular homeostasis.