Circular RNA circASH1L(4,5) protects microRNA-129-5p from target-directed microRNA degradation in human skin wound healing.

Abstract

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.