Integrative small and long RNA omics analysis of human healing and nonhealing wounds discovers cooperating microRNAs as therapeutic targets
- Karolinska Institute, Sweden
- Chinese Academy of Medical Sciences and Peking Union Medical College, China
- University of Miami, United States
- Karolinska University Hospital, Sweden
Abstract
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 paired small RNA and long RNA sequencing and integrative omics analysis in human tissue samples, including matched skin and acute wounds collected at each healing stage and chronic non-healing venous ulcers (VU). On the basis of the findings, we developed a compendium (https://www.xulandenlab.com/humanwounds-mirna-mrna), which will be an open, comprehensive resource to broadly aid wound healing research. With this first clinical, wound-centric resource of miRs and mRNAs, we identified 17 pathologically relevant miRs that exhibited abnormal VU expression and displayed their targets enriched explicitly in the VU gene signature. Intermeshing regulatory networks controlled by these miRs revealed their high cooperativity in contributing to chronic wound pathology characterized by persistent inflammation and proliferative phase initiation failure. Furthermore, we demonstrated that miR-34a, miR-424, and miR-516, upregulated in VU, cooperatively suppressed keratinocyte migration and growth while promoting inflammatory response. By combining miR expression patterns with their specific target gene expression context, we identified miRs highly relevant to VU pathology. Our study opens the possibility of developing innovative wound treatment that targets pathologically relevant cooperating miRs to attain higher therapeutic efficacy and specificity.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE174661 and GSE196773.The analyzed dataset is presented with an online R Shiny app and can be accessed through a browsable web portal (https://www.xulandenlab.com/humanwounds-mirna-mrna).The analysis source code is available at https://github.com/Zhuang-Bio/miRNAprofiling.Source data files have been provided by excel files for figures 1c, 1d, 1e, 2a, 2b, 2c, 2d, 2e, 4a, 4b, 5b-j, 6k, 8, 9 and figure supplements 2-2, 2-4c, 6, 7a, b lower panels.
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Funding
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Written informed consent was obtained from all the donors to collect and use the tissue samples.The study was approved by the Stockholm Regional Ethics Committee and conducted according to the Declaration of Helsinki's principles.
Copyright
© 2022, Liu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Integrative small and long RNA omics analysis of human healing and nonhealing wounds discovers cooperating microRNAs as therapeutic targets
eLife 11:e80322.
https://doi.org/10.7554/eLife.80322
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