PUBLICATION

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

Authors
Ranjan, G., Sehgal, P., Scaria, V., Sivasubbu, S.
ID
ZDB-PUB-241003-10
Date
2024
Source
EMBO reports   25(11): 4950-4978 (Journal)
Registered Authors
Sivasubbu, Sridhar
Keywords
Cardiovascular, Endothelial Cell, Hemorrhage, Synteny lncRNA, Zebrafish
MeSH Terms
  • Animals
  • Genetic Loci
  • RNA, Long Noncoding*/genetics
  • RNA, Long Noncoding*/metabolism
  • Zebrafish Proteins*/genetics
  • Zebrafish Proteins*/metabolism
  • Blood Coagulation*/genetics
  • Endothelial Cells/metabolism
  • Enhancer Elements, Genetic/genetics
  • Capillary Permeability/genetics
  • NF-kappa B/metabolism
  • Gene Expression Regulation
  • Zebrafish*/genetics
  • Humans
  • Epigenesis, Genetic*
(all 15)
PubMed
39358551 Full text @ EMBO Rep.
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.
Genes / Markers
Figures
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
gib007
    Small Deletion
    sd2TgTransgenic Insertion
      y1TgTransgenic Insertion
        1 - 3 of 3
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        Human Disease / Model
        No data available
        Sequence Targeting Reagents
        No data available
        Fish
        No data available
        Antibodies
        No data available
        Orthology
        No data available
        Engineered Foreign Genes
        Marker Marker Type Name
        DsRedEFGDsRed
        EGFPEFGEGFP
        1 - 2 of 2
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        Mapping