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Updated: Jul 27, 2025
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Detection of Alternative Splicing During Epithelial-Mesenchymal Transition
Published on: October 9, 2014
13.0K
Heterogeneous expression of alternatively spliced lncRNA mediates vascular smooth cell plasticity
Jaimie M Mayner1, Evan M Masutani1, Elena Demeester2
1Chien-Lay Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093.
Summary
Genetic variations in the 9p21.3 locus are linked to coronary artery disease. Long noncoding RNA ANRIL may influence vascular smooth muscle cell function, explaining disease risk heterogeneity.
Area of Science:
- Genetics
- Molecular Biology
- Cardiovascular Disease Research
Background:
- Polymorphisms at the 9p21.3 locus strongly correlate with coronary artery disease (CAD).
- The noncoding nature of this locus makes its disease mechanism enigmatic.
- The long noncoding RNA (lncRNA) ANRIL, located in 9p21.3, is a potential regulator of vascular smooth muscle cell (VSMC) phenotype and CAD risk.
Purpose of the Study:
- To investigate the role of ANRIL in mediating the effects of 9p21.3 risk variants on VSMC phenotype.
- To understand the heterogeneity observed in VSMCs derived from patients with different 9p21.3 haplotypes.
Main Methods:
- Utilized induced pluripotent stem cell-derived VSMCs from patients with homozygous risk or nonrisk haplotypes, and isogenic knockouts.
- Analyzed VSMC subpopulations based on adhesion properties (weakly adherent/synthetic vs. strongly adherent/contractile).
- Performed gene expression analysis, focusing on Rho GTPase-associated genes, and ANRIL isoform expression and functional assays.
Main Results:
- Significant heterogeneity in morphology, proliferation, contraction, and adhesion was observed in risk haplotype VSMCs.
- Risk VSMCs sorted by adhesion revealed distinct synthetic (weakly adherent) and contractile (strongly adherent) subpopulations.
- >90% of differentially expressed genes were associated with Rho GTPases, indicating a role in contractility.
- Weakly adherent subpopulations showed higher expression of short ANRIL isoforms.
- Overexpression of ANRIL in knockout cells suppressed adhesion, contractility, and alpha-smooth muscle actin (αSMA) expression.
Conclusions:
- Variable lncRNA ANRIL penetrance, influenced by haplotype and isoform expression, may drive functional heterogeneity in VSMCs.
- This heterogeneity in VSMC phenotype contributes to the complex pathology of coronary artery disease.
- ANRIL's regulatory role in VSMC contractility and adhesion offers potential therapeutic targets for CAD.
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