RT Journal Article
SR Electronic
T1 Genome-wide, integrative analysis of microRNA-mediated gene regulation in human wounds reveals cooperating microRNAs as therapeutic targets
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.12.17.473103
DO 10.1101/2021.12.17.473103
A1 Zhuang Liu
A1 Letian Zhang
A1 Maria-Alexandra Toma
A1 Dongqing Li
A1 Xiaowei Bian
A1 Irena Pastar
A1 Marjana Tomic-Canic
A1 Pehr Sommar
A1 Ning Xu Landén
YR 2021
UL http://biorxiv.org/content/early/2021/12/17/2021.12.17.473103.abstract
AB MicroRNAs (miR), as important epigenetic control factors, reportedly regulate wound repair. However, our insufficient knowledge of clinically relevant miRs hinders their potential therapeutic use. For this, we performed miR and mRNA paired expression profiling in human acute wounds and chronic non-healing venous ulcers (VU) and presented our findings on a browsable web portal (http://130.229.28.87/shiny/miRNA_Xulab/). Integrative miR and mRNA-omics analysis unraveled miR-mediated gene regulatory networks in each repair phase of the wound repair process. Importantly, we identified 17 pathologically relevant miRs exhibiting abnormal expression in VU and displaying their targetome enriched in the VU gene signature. Study of the targetome and functions of eight clinically relevant miRs in skin cells revealed that the miRs upregulated in VU (i.e., miR-34a/c-5p, miR-424-5p, miR-450-5p, miR-7704, and miR-516-5p) promoted inflammation but inhibited proliferation. In contrast, the miRs downregulated in VU (i.e., miR-218-5p and miR-96-5p) were required for cell growth and activation. Moreover, we demonstrated miR-34a, miR-424, and miR-516 cooperativity in regulating keratinocyte growth and inflammatory response. Collectively, our study suggests that VU-dysregulated miRs cooperatively contribute to stalled wound healing characterized by failed transition from inflammatory-to-proliferative phase. Targeting cooperating miRNAs provide mew opportunity for development of clinically-relevant targeted therapy to attain higher therapeutic efficacy and specificity.Competing Interest StatementThe authors have declared no competing interest.