The Poly-cistronic miR-23-27-24 Complexes Target Endothelial Cell Junctions: Differential Functional and Molecular Effects of miR-23a and miR-23b
The regulation of function of endothelial cell–cell junctions is fundamental in sustaining vascular integrity. The polycistronic microRNA (miR) complexes containing miR-23a-27a-24-2, and 23b-27b-24-1 are predicted to target the majority of major endothelial junctional proteins. We focus on miR-23a a...
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| Format: | Article |
| Language: | English |
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Elsevier
2016-01-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253117300768 |
| _version_ | 1828761927568850944 |
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| author | Jia Li Yang Zhao Ying Lu William Ritchie Georges Grau Mathew A Vadas Jennifer R Gamble |
| author_facet | Jia Li Yang Zhao Ying Lu William Ritchie Georges Grau Mathew A Vadas Jennifer R Gamble |
| author_sort | Jia Li |
| collection | DOAJ |
| description | The regulation of function of endothelial cell–cell junctions is fundamental in sustaining vascular integrity. The polycistronic microRNA (miR) complexes containing miR-23a-27a-24-2, and 23b-27b-24-1 are predicted to target the majority of major endothelial junctional proteins. We focus on miR-23a and miR-23b, and investigate the functional effects of these miRs on junctions. While miR-23a and 23b only differ by 1 nucleotide (g19) outside the seed region and thus are predicted to have the same targets, they function differently with miR-23a inhibiting permeability and miR-23b inhibiting angiogenesis. Both miRs target the junctional attractive molecule (tight junction protein 2) ZO-2 and the repulsive molecule junctional adhesion molecule C (JAM-C), although the inhibition of JAM-C by miR-23a is more profound than by miR-23b. The difference in potency is attributable to differences at g19 since a mutation of the t17, the g19 binding site of miR-23b in the 3′UTR of JAM-C restores identity. We also show that the pattern of expression of miR-23a and miR-23b and their targets are different. Thus, the paralogues miR-23a and miR-23b can have profoundly different effects on endothelial cell function due at least partially to selective effects on target proteins and differences in expression patterns of the miRs. This work exposes a hitherto unappreciated complexity in therapeutically targeting miRs. |
| first_indexed | 2024-12-11T01:36:28Z |
| format | Article |
| id | doaj.art-d5ce49bcb71c46cca8edb4ddd75dc84c |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-11T01:36:28Z |
| publishDate | 2016-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-d5ce49bcb71c46cca8edb4ddd75dc84c2022-12-22T01:25:11ZengElsevierMolecular Therapy: Nucleic Acids2162-25312016-01-015C10.1038/mtna.2016.62The Poly-cistronic miR-23-27-24 Complexes Target Endothelial Cell Junctions: Differential Functional and Molecular Effects of miR-23a and miR-23bJia Li0Yang Zhao1Ying Lu2William Ritchie3Georges Grau4Mathew A Vadas5Jennifer R Gamble6Centre for the Endothelium, Vascular Biology Program, Centenary Institute, University of Sydney, Sydney, AustraliaCentre for the Endothelium, Vascular Biology Program, Centenary Institute, University of Sydney, Sydney, AustraliaCentre for the Endothelium, Vascular Biology Program, Centenary Institute, University of Sydney, Sydney, AustraliaBioinformatics Laboratory, Centenary Institute, University of Sydney, Sydney, AustraliaDepartment of Pathology, Faculty of Medicine, School of Medical Sciences, University of Sydney, Sydney, AustraliaCentre for the Endothelium, Vascular Biology Program, Centenary Institute, University of Sydney, Sydney, AustraliaCentre for the Endothelium, Vascular Biology Program, Centenary Institute, University of Sydney, Sydney, AustraliaThe regulation of function of endothelial cell–cell junctions is fundamental in sustaining vascular integrity. The polycistronic microRNA (miR) complexes containing miR-23a-27a-24-2, and 23b-27b-24-1 are predicted to target the majority of major endothelial junctional proteins. We focus on miR-23a and miR-23b, and investigate the functional effects of these miRs on junctions. While miR-23a and 23b only differ by 1 nucleotide (g19) outside the seed region and thus are predicted to have the same targets, they function differently with miR-23a inhibiting permeability and miR-23b inhibiting angiogenesis. Both miRs target the junctional attractive molecule (tight junction protein 2) ZO-2 and the repulsive molecule junctional adhesion molecule C (JAM-C), although the inhibition of JAM-C by miR-23a is more profound than by miR-23b. The difference in potency is attributable to differences at g19 since a mutation of the t17, the g19 binding site of miR-23b in the 3′UTR of JAM-C restores identity. We also show that the pattern of expression of miR-23a and miR-23b and their targets are different. Thus, the paralogues miR-23a and miR-23b can have profoundly different effects on endothelial cell function due at least partially to selective effects on target proteins and differences in expression patterns of the miRs. This work exposes a hitherto unappreciated complexity in therapeutically targeting miRs.http://www.sciencedirect.com/science/article/pii/S2162253117300768miR-23-27-24endothelial cellscell-cell junctionsmiR-23 |
| spellingShingle | Jia Li Yang Zhao Ying Lu William Ritchie Georges Grau Mathew A Vadas Jennifer R Gamble The Poly-cistronic miR-23-27-24 Complexes Target Endothelial Cell Junctions: Differential Functional and Molecular Effects of miR-23a and miR-23b Molecular Therapy: Nucleic Acids miR-23-27-24 endothelial cells cell-cell junctions miR-23 |
| title | The Poly-cistronic miR-23-27-24 Complexes Target Endothelial Cell Junctions: Differential Functional and Molecular Effects of miR-23a and miR-23b |
| title_full | The Poly-cistronic miR-23-27-24 Complexes Target Endothelial Cell Junctions: Differential Functional and Molecular Effects of miR-23a and miR-23b |
| title_fullStr | The Poly-cistronic miR-23-27-24 Complexes Target Endothelial Cell Junctions: Differential Functional and Molecular Effects of miR-23a and miR-23b |
| title_full_unstemmed | The Poly-cistronic miR-23-27-24 Complexes Target Endothelial Cell Junctions: Differential Functional and Molecular Effects of miR-23a and miR-23b |
| title_short | The Poly-cistronic miR-23-27-24 Complexes Target Endothelial Cell Junctions: Differential Functional and Molecular Effects of miR-23a and miR-23b |
| title_sort | poly cistronic mir 23 27 24 complexes target endothelial cell junctions differential functional and molecular effects of mir 23a and mir 23b |
| topic | miR-23-27-24 endothelial cells cell-cell junctions miR-23 |
| url | http://www.sciencedirect.com/science/article/pii/S2162253117300768 |
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