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.

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Chicken is recognized as an excellent model for studies of genetic mechanism of phenotypic and genomic evolution, with large effective population size and strong human-driven selection. In the present study, we performed Extended Haplotype Homozygosity (EHH) tests to identify significant core regions employing 600K SNP Chicken chip in an F2 population of 1,534 hens, which was derived from reciprocal crosses between White Leghorn and Dongxiang chicken. Results indicated that a total of 49,151 core regions with an average length of 9.79 Kb were identified, which occupied approximately 52.15% of genome across all autosomes, and 806 significant core regions attracted us mostly. Genes in candidate regions may experience positive selection and were considered to have possible influence on beneficial economic traits. A panel of genes including AASDHPPT, GDPD5, PAR3, SOX6, GPC1 and a signal pathway of AKT1 were detected with the most extreme P-values. Further enrichment analyses indicated that these genes were associated with immune function, sensory organ development and neurogenesis, and may have experienced positive selection in chicken. Moreover, some of core regions exactly overlapped with genes excavated in our previous GWAS, suggesting that these genes have undergone positive selection may affect egg production. Findings in our study could draw a comparatively integrate genome-wide map of selection signature in the chicken genome, and would be worthy for explicating the genetic mechanisms of phenotypic diversity in poultry breeding.

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After a skin injury, keratinocytes switch from a state of homeostasis to one of regeneration leading to the reconstruction of the epidermal barrier. The regulatory mechanism of gene expression underpinning this key switch during human skin wound healing is enigmatic. Long noncoding RNAs (lncRNAs) constitute a new horizon in the understanding of the regulatory programmes encoded in the mammalian genome. By comparing the transcriptome of an acute human wound and skin from the same donor as well as keratinocytes isolated from these paired tissue samples, we generated a list of lncRNAs showing changed expression in keratinocytes during wound repair. Our study focused on HOXC13-AS, a recently evolved human lncRNA specifically expressed in epidermal keratinocytes, and we found that its expression was temporally downregulated during wound healing. In line with its enrichment in suprabasal keratinocytes, HOXC13-AS was found to be increasingly expressed during keratinocyte differentiation, but its expression was reduced by EGFR signalling. After HOXC13-AS knockdown or overexpression in human primary keratinocytes undergoing differentiation induced by cell suspension or calcium treatment and in organotypic epidermis, we found that keratinocyte differentiation was promoted, while the cell inflammatory response was suppressed. Moreover, RNA pull-down assays followed by mass spectrometry and RNA immunoprecipitation analysis revealed that mechanistically HOXC13-AS sequestered the coat complex subunit alpha (COPA) protein and interfered with Golgi-to-endoplasmic reticulum (ER) molecular transport, resulting in ER stress and enhanced keratinocyte differentiation. In summary, we identified HOXC13-AS as a crucial regulator of human epidermal differentiation.

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