Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes
Alexander A. Merleev, … , Johann E. Gudjonsson, Emanual Maverakis
Alexander A. Merleev, … , Johann E. Gudjonsson, Emanual Maverakis
Published July 28, 2022
Citation Information: JCI Insight. 2022;7(16):e159762. https://doi.org/10.1172/jci.insight.159762.
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Resource and Technical Advance Dermatology

Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes

Abstract

The epidermis is the outermost layer of skin. Here, we used targeted lipid profiling to characterize the biogeographic alterations of human epidermal lipids across 12 anatomically distinct body sites, and we used single-cell RNA-Seq to compare keratinocyte gene expression at acral and nonacral sites. We demonstrate that acral skin has low expression of EOS acyl-ceramides and the genes involved in their synthesis, as well as low expression of genes involved in filaggrin and keratin citrullination (PADI1 and PADI3) and corneodesmosome degradation, changes that are consistent with increased corneocyte retention. Several overarching principles governing epidermal lipid expression were also noted. For example, there was a strong negative correlation between the expression of 18-carbon and 22-carbon sphingoid base ceramides. Disease-specific alterations in epidermal lipid gene expression and their corresponding alterations to the epidermal lipidome were characterized. Lipid biomarkers with diagnostic utility for inflammatory and precancerous conditions were identified, and a 2-analyte diagnostic model of psoriasis was constructed using a step-forward algorithm. Finally, gene coexpression analysis revealed a strong connection between lipid and immune gene expression. This work highlights (a) mechanisms by which the epidermis is uniquely adapted for the specific environmental insults encountered at different body surfaces and (b) how inflammation-associated alterations in gene expression affect the epidermal lipidome.

Authors

Alexander A. Merleev, Stephanie T. Le, Claire Alexanian, Atrin Toussi, Yixuan Xie, Alina I. Marusina, Steven M. Watkins, Forum Patel, Allison C. Billi, Julie Wiedemann, Yoshihiro Izumiya, Ashish Kumar, Ranjitha Uppala, J. Michelle Kahlenberg, Fu-Tong Liu, Iannis E. Adamopoulos, Elizabeth A. Wang, Chelsea Ma, Michelle Y. Cheng, Halani Xiong, Amanda Kirane, Guillaume Luxardi, Bogi Andersen, Lam C. Tsoi, Carlito B. Lebrilla, Johann E. Gudjonsson, Emanual Maverakis

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Figure 6

Transcriptome alterations in acral keratinocytes provide insight into the distinctive epidermal features of palmoplantar skin.

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Transcriptome alterations in acral keratinocytes provide insight into th...
(A) UMAP dimensionality reduction plots of single-cell RNA-Seq data. Single-cell RNA-Seq was performed on keratinocytes isolated from paired palm and trunk skin biopsies. Each dot represents an individual keratinocyte (basal [palm, green; trunk, yellow]; spinous [palm, blue; trunk, pink]; and granular [palm, red; trunk, orange] layers). Cells expressing the noted gene of interest are depicted in purple. Dashed circles are drawn around the keratinocyte population in which the expression of the noted gene is most strongly upregulated. Arrows to the left of gene names represents the directionality of gene expression in acral keratinocytes. (B) Single-cell RNA-Seq data presented as box-and-whisker plots. Each individual data point represents the number of reads that mapped to the indicated gene in a single granular layer keratinocyte. (C) Paired biopsies obtained from palm and trunk skin were evaluated by RNA-Seq. Results of select genes relevant to keratin citrullination and corneodesmosome degradation are presented as box-and-whisker plots.