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Published on: February 15, 2020
Integrated Transcriptomic and Single-Cell Analyses Link ATP7A, a Cuproptosis-Related Hub Gene, to ECM-Adhesion
Shiyang Li1,2, Wei Wan3, Ting Meng1,2
1Department of Dermatology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, People's Republic of China.
Objective:
To investigate the link between UVB-induced skin photodamage and cuproptosis, and identify key regulatory genes.
Methods:
Transcriptomic data from UVB-irradiated human skin (GSE41078) were obtained from GEO. Differentially expressed genes (DEGs) were identified, followed by GO and KEGG enrichment, and WGCNA. Key regulators were defined by intersecting DEGs, cuproptosis-related genes (CRGs), and the WGCNA module most correlated with photodamage. Single-cell RNA-seq data (GSE289389) were used to assess ATP7A expression in keratinocytes and to infer cell-cell communication (CellChat), focusing on ECM and adhesion signaling. Hub genes were validated via qRT-PCR and Western blot in UVB-induced acute photodamage cells and mouse models.
Results:
Examination of the GSE41078 dataset revealed 509 DEGs associated with photodamage. WGCNA identified the blue module as most strongly correlated with photodamage. Cross-referencing 978 core module genes with 55 CRGs and 509 DEGs identified a single hub gene, ATPase copper transporting alpha (ATP7A). Single-cell analysis confirmed significant ATP7A downregulation after UVB exposure (p = 1.83 × 10-5) and showed that ATP7A-high keratinocytes exhibited stronger integration with stromal cells via enhanced ECM-adhesion signaling (e.g. collagen, laminin), whereas ATP7A-low cells displayed weakened responsiveness to microenvironmental cues. Experimental confirmation suggested that both mRNA and protein expression of ATP7A were markedly diminished in photodamaged cellular and mouse models (P < 0.05), aligning with the computational predictions.
Conclusion:
This study suggests a potential association between ATP7A downregulation and UVB-induced photodamage with possible relevance to cuproptosis-related pathways. ATP7A downregulation is associated with reduced ECM-adhesion signaling interactions in keratinocytes, as indicated by CellChat. This analysis provides new clues to the mechanism of photodamage and suggests that ATP7A may be involved in the functional regulation of skin photodamage.
Insights
This study links UVB-induced skin photodamage to ATP7A downregulation, potentially involving cuproptosis pathways. Reduced ATP7A impacts keratinocyte signaling and skin cell communication.
Area of Science:
- Dermatology
- Molecular Biology
- Biochemistry
Background:
- UVB radiation causes significant skin photodamage, affecting cellular functions and gene expression.
- Cuproptosis, a copper-dependent cell death pathway, is increasingly recognized for its role in various biological processes.
- Understanding the molecular mechanisms underlying skin photodamage is crucial for developing effective preventative and therapeutic strategies.
Purpose of the Study:
- To investigate the association between UVB-induced skin photodamage and cuproptosis.
- To identify key regulatory genes involved in the photodamage process.
- To elucidate the role of ATP7A in skin photodamage and cellular signaling.
Main Methods:
- Analysis of transcriptomic data (GSE41078) from UVB-irradiated human skin.
- Identification of differentially expressed genes (DEGs), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis.
- Weighted gene co-expression network analysis (WGCNA) to identify key modules and hub genes.
- Single-cell RNA sequencing (scRNA-seq) analysis (GSE289389) to assess ATP7A expression and cell-cell communication.
- Validation of hub gene expression using qRT-PCR and Western blot in cellular and mouse models.
Main Results:
- A total of 509 DEGs were identified in photodamaged skin.
- WGCNA highlighted a blue module strongly correlated with photodamage.
- ATPase copper transporting alpha (ATP7A) was identified as a single hub gene by integrating DEGs, cuproptosis-related genes (CRGs), and the WGCNA module.
- ATP7A expression was significantly downregulated in UVB-exposed keratinocytes and in photodamaged cellular and mouse models.
- Downregulation of ATP7A was associated with reduced extracellular matrix (ECM) and adhesion signaling in keratinocytes.
Conclusions:
- ATP7A downregulation is potentially linked to UVB-induced skin photodamage and may be associated with cuproptosis-related pathways.
- Reduced ATP7A expression in keratinocytes correlates with diminished ECM-adhesion signaling and impaired responsiveness to microenvironmental cues.
- ATP7A may play a functional role in regulating skin photodamage, offering new insights into its underlying mechanisms.
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