Adenosine-to-Inosine Editing of Vasoactive MicroRNAs Alters Their Targetome and Function in Ischemia
Adenosine-to-inosine (A-to-I) editing in the seed sequence of microRNAs can shift the microRNAs’ targetomes and thus their function. Using public RNA-sequencing data, we identified 35 vasoactive microRNAs that are A-to-I edited. We quantified A-to-I editing of the primary (pri-)microRNAs in vascular...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2020-09-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253120302092 |
| _version_ | 1818466864050733056 |
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| author | Reginald V.C.T. van der Kwast Laura Parma M. Leontien van der Bent Eva van Ingen Fabiana Baganha Hendrika A.B. Peters Eveline A.C. Goossens Karin H. Simons Meindert Palmen Margreet R. de Vries Paul H.A. Quax A. Yaël Nossent |
| author_facet | Reginald V.C.T. van der Kwast Laura Parma M. Leontien van der Bent Eva van Ingen Fabiana Baganha Hendrika A.B. Peters Eveline A.C. Goossens Karin H. Simons Meindert Palmen Margreet R. de Vries Paul H.A. Quax A. Yaël Nossent |
| author_sort | Reginald V.C.T. van der Kwast |
| collection | DOAJ |
| description | Adenosine-to-inosine (A-to-I) editing in the seed sequence of microRNAs can shift the microRNAs’ targetomes and thus their function. Using public RNA-sequencing data, we identified 35 vasoactive microRNAs that are A-to-I edited. We quantified A-to-I editing of the primary (pri-)microRNAs in vascular fibroblasts and endothelial cells. Nine pri-microRNAs were indeed edited, and editing consistently increased under ischemia. We determined mature microRNA editing for the highest expressed microRNAs, i.e., miR-376a-3p, miR-376c-3p, miR-381-3p, and miR-411-5p. All four mature microRNAs were edited in their seed sequence. We show that both ADAR1 and ADAR2 (adenosine deaminase acting on RNA 1 and RNA 2) can edit pri-microRNAs in a microRNA-specific manner. MicroRNA editing also increased under ischemia in vivo in a murine hindlimb ischemia model and ex vivo in human veins. For each edited microRNA, we confirmed a shift in targetome. Expression of the edited microRNA targetomes, not the wild-type targetomes, was downregulated under ischemia in vivo. Furthermore, microRNA editing enhanced angiogenesis in vitro and ex vivo. In conclusion, we show that microRNA A-to-I editing is a widespread phenomenon, induced by ischemia. Each editing event results in a novel microRNA with a unique targetome, leading to increased angiogenesis. |
| first_indexed | 2024-04-13T21:02:28Z |
| format | Article |
| id | doaj.art-2209272f4f534aa0b0f07a3770ab3c50 |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-04-13T21:02:28Z |
| publishDate | 2020-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-2209272f4f534aa0b0f07a3770ab3c502022-12-22T02:30:05ZengElsevierMolecular Therapy: Nucleic Acids2162-25312020-09-0121932953Adenosine-to-Inosine Editing of Vasoactive MicroRNAs Alters Their Targetome and Function in IschemiaReginald V.C.T. van der Kwast0Laura Parma1M. Leontien van der Bent2Eva van Ingen3Fabiana Baganha4Hendrika A.B. Peters5Eveline A.C. Goossens6Karin H. Simons7Meindert Palmen8Margreet R. de Vries9Paul H.A. Quax10A. Yaël Nossent11Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, the NetherlandsDepartment of Surgery, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, the NetherlandsDepartment of Surgery, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, the NetherlandsDepartment of Surgery, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, the NetherlandsDepartment of Surgery, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, the NetherlandsDepartment of Surgery, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, the NetherlandsDepartment of Surgery, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, the NetherlandsDepartment of Surgery, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, the NetherlandsDepartment of Cardiothoracic Surgery, Leiden University Medical Center, 2333 ZA Leiden, the NetherlandsDepartment of Surgery, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, the NetherlandsDepartment of Surgery, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, the NetherlandsDepartment of Surgery, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands; Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria; Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria; Corresponding author: A. Yaël Nossent, Department of Surgery, D6-28, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.Adenosine-to-inosine (A-to-I) editing in the seed sequence of microRNAs can shift the microRNAs’ targetomes and thus their function. Using public RNA-sequencing data, we identified 35 vasoactive microRNAs that are A-to-I edited. We quantified A-to-I editing of the primary (pri-)microRNAs in vascular fibroblasts and endothelial cells. Nine pri-microRNAs were indeed edited, and editing consistently increased under ischemia. We determined mature microRNA editing for the highest expressed microRNAs, i.e., miR-376a-3p, miR-376c-3p, miR-381-3p, and miR-411-5p. All four mature microRNAs were edited in their seed sequence. We show that both ADAR1 and ADAR2 (adenosine deaminase acting on RNA 1 and RNA 2) can edit pri-microRNAs in a microRNA-specific manner. MicroRNA editing also increased under ischemia in vivo in a murine hindlimb ischemia model and ex vivo in human veins. For each edited microRNA, we confirmed a shift in targetome. Expression of the edited microRNA targetomes, not the wild-type targetomes, was downregulated under ischemia in vivo. Furthermore, microRNA editing enhanced angiogenesis in vitro and ex vivo. In conclusion, we show that microRNA A-to-I editing is a widespread phenomenon, induced by ischemia. Each editing event results in a novel microRNA with a unique targetome, leading to increased angiogenesis.http://www.sciencedirect.com/science/article/pii/S2162253120302092microRNAA-to-I editingischemiaperipheral artery diseaseangiogenesistarget gene regulation |
| spellingShingle | Reginald V.C.T. van der Kwast Laura Parma M. Leontien van der Bent Eva van Ingen Fabiana Baganha Hendrika A.B. Peters Eveline A.C. Goossens Karin H. Simons Meindert Palmen Margreet R. de Vries Paul H.A. Quax A. Yaël Nossent Adenosine-to-Inosine Editing of Vasoactive MicroRNAs Alters Their Targetome and Function in Ischemia Molecular Therapy: Nucleic Acids microRNA A-to-I editing ischemia peripheral artery disease angiogenesis target gene regulation |
| title | Adenosine-to-Inosine Editing of Vasoactive MicroRNAs Alters Their Targetome and Function in Ischemia |
| title_full | Adenosine-to-Inosine Editing of Vasoactive MicroRNAs Alters Their Targetome and Function in Ischemia |
| title_fullStr | Adenosine-to-Inosine Editing of Vasoactive MicroRNAs Alters Their Targetome and Function in Ischemia |
| title_full_unstemmed | Adenosine-to-Inosine Editing of Vasoactive MicroRNAs Alters Their Targetome and Function in Ischemia |
| title_short | Adenosine-to-Inosine Editing of Vasoactive MicroRNAs Alters Their Targetome and Function in Ischemia |
| title_sort | adenosine to inosine editing of vasoactive micrornas alters their targetome and function in ischemia |
| topic | microRNA A-to-I editing ischemia peripheral artery disease angiogenesis target gene regulation |
| url | http://www.sciencedirect.com/science/article/pii/S2162253120302092 |
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