PT  - JOURNAL ARTICLE
AU  - Letian Zhang
AU  - Minna Piipponen
AU  - Zhuang Liu
AU  - Dongqing Li
AU  - Xiaowei Bian
AU  - Maria A. Toma
AU  - Pehr Sommar
AU  - Ning Xu Landén
TI  - Human skin specific long noncoding RNA <em>HOXC13-AS</em> regulates epidermal differentiation by interfering with Golgi-ER retrograde transport
AID  - 10.1101/2022.07.04.498689
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.07.04.498689
4099  - http://biorxiv.org/content/early/2022/07/04/2022.07.04.498689.short
4100  - http://biorxiv.org/content/early/2022/07/04/2022.07.04.498689.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.