Circular RNA circASH1L(4,5) protects microRNA-129-5p from target-directed microRNA degradation in human skin wound healing
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Background
Skin wound healing involves a complex gene expression programme that remains largely undiscovered in humans. Circular RNAs (circRNAs) and microRNAs (miRNAs) are key players in this process.
Objectives
To understand the functions and potential interactions of circRNAs and miRNAs in human skin wound healing.
Methods
CircRNA, linear RNA and miRNA expression in human acute and chronic wounds were analysed with RNA sequencing and quantitative reverse transcription polymerase chain reaction. The roles of circASH1L(4,5) and miR-129-5p were studied in human primary keratinocytes (proliferation and migration assays, microarray analysis) and ex vivo wound models (histological analysis). The interaction between circASH1L(4,5) and miR-129-5p was examined using luciferase reporter and RNA pulldown assays.
Results
We identified circASH1L(4,5) and its interaction with miR-129-5p, both of which increased during human skin wound healing. Unlike typical miRNA sponging, circASH1L enhanced miR-129 stability and silencing activity by protecting it from target-directed degradation triggered by NR6A1 mRNA. Transforming growth factor-β signalling – crucial in wound healing – promoted circASH1L expression while suppressing NR6A1, thereby increasing the abundance of miR-129 at the post-transcriptional level. CircASH1L and miR-129 enhanced keratinocyte migration and proliferation, crucial processes for the re-epithelialization of human wounds.
Conclusions
Our study uncovered a novel role for circRNAs as protectors of miRNAs and highlights the importance of regulated miRNA degradation in skin wound healing.
