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
-
- Zebrafish*/genetics
- Animals
- Epigenesis, Genetic*
- Blood Coagulation*/genetics
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Humans
- Gene Expression Regulation
- Enhancer Elements, Genetic/genetics
- Capillary Permeability/genetics
- RNA, Long Noncoding*/genetics
- RNA, Long Noncoding*/metabolism
- NF-kappa B/metabolism
- Genetic Loci
- Endothelial Cells/metabolism
- PubMed
- 39358551 Full text @ EMBO Rep.
Citation
Ranjan, G., Sehgal, P., Scaria, V., Sivasubbu, S. (2024) SCAR-6 elncRNA locus epigenetically regulates PROZ and modulates coagulation and vascular function. EMBO reports. 25(11):4950-4978.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping