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PubMed · 39358551

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

Gyan Ranjan·Paras Sehgal·Vinod Scaria·Sridhar Sivasubbu
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Abstract

In this study, we characterize a novel lncRNA-producing gene locus that we name Syntenic Cardiovascular Conserved Region-Associated lncRNA-6 (scar-6) and functionally validate its role in coagulation and cardiovascular function. A 12-bp deletion of the scar-6 locus in zebrafish (scar-6gib007Δ12/Δ12) results in cranial hemorrhage and vascular permeability. Overexpression, knockdown and rescue with the scar-6 lncRNA modulates hemostasis in zebrafish. Molecular investigation reveals that the scar-6 lncRNA acts as an enhancer lncRNA (elncRNA), and controls the expression of prozb, an inhibitor of factor Xa, through an enhancer element in the scar-6 locus. The scar-6 locus suppresses loop formation between prozb and scar-6 sequences, which might be facilitated by the methylation of CpG islands via the prdm14-PRC2 complex whose binding to the locus might be stabilized by the scar-6 elncRNA transcript. Binding of prdm14 to the scar-6 locus is impaired in scar-6gib007Δ12/Δ12 zebrafish. Finally, activation of the PAR2 receptor in scar-6gib007Δ12/Δ12 zebrafish triggers NF-κB-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.

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AnimalsZebrafishRNA, Long NoncodingZebrafish ProteinsEpigenesis, GeneticBlood CoagulationHumansGenetic LociNF-kappa BGene Expression RegulationCapillary PermeabilityEndothelial CellsEnhancer Elements, GeneticCardiovascularEndothelial CellHemorrhageSynteny lncRNAJournal Article

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Gyan Ranjan, Paras Sehgal, Vinod Scaria, Sridhar Sivasubbu. 2024-10-02. SCAR-6 elncRNA locus epigenetically regulates PROZ and modulates coagulation and vascular function.. https://doi.org/10.1038/s44319-024-00272-w

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