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

Background: Skin wound healing involves a complex gene expression program 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 analyzed using RNA sequencing and qRT-PCR. 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 pull-down 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. TGF-β signaling, crucial in wound healing, promoted circASH1L expression while suppressing NR6A1, thereby increasing miR-129 abundance at the post-transcriptional level. CircASH1L and miR-129 enhanced keratinocyte migration and proliferation, crucial for re-epithelialization of human wounds.

Conclusions: Our study uncovers a novel role for circRNAs as protectors of miRNAs and highlights the importance of regulated miRNA degradation in skin wound healing.