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Published on: June 15, 2018
Adenosine-to-Inosine Editing of Vasoactive MicroRNAs Alters Their Targetome and Function in Ischemia
Reginald V C T van der Kwast1, Laura Parma1, M Leontien van der Bent1
1Department 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.
Abstract:
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.
Insights
MicroRNA adenosine-to-inosine (A-to-I) editing, induced by ischemia, alters microRNA function by changing their targets. This widespread editing enhances blood vessel formation (angiogenesis).
Area of Science:
- Molecular Biology
- Genetics
- Cardiovascular Research
Background:
- Adenosine-to-inosine (A-to-I) editing in microRNAs can alter their function by changing target recognition.
- Vascular conditions like ischemia are known to affect gene expression and cellular function.
Purpose of the Study:
- To investigate the role and impact of A-to-I editing in microRNAs within the vascular system, particularly under ischemic conditions.
- To determine if microRNA editing influences angiogenesis.
Main Methods:
- Analysis of public RNA-sequencing data to identify edited vasoactive microRNAs.
- Quantification of pri-microRNA and mature microRNA editing in vascular cells and in vivo models.
- Assessment of microRNA targetome shifts and functional effects on angiogenesis.
Main Results:
- Identified 35 vasoactive microRNAs undergoing A-to-I editing, with editing levels increasing under ischemia.
- Confirmed editing in specific mature microRNAs (miR-376a-3p, miR-376c-3p, miR-381-3p, miR-411-5p) and identified ADAR1/ADAR2 as key enzymes.
- Demonstrated that microRNA editing shifts targetomes, leading to downregulation of edited targets under ischemia and enhanced angiogenesis in vitro and ex vivo.
Conclusions:
- MicroRNA A-to-I editing is a significant, ischemia-induced mechanism in the vascular system.
- Each editing event generates a novel microRNA with a distinct targetome, influencing cellular responses to ischemia.
- MicroRNA editing promotes angiogenesis, suggesting a therapeutic potential for vascular repair.
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