An Extended Transcriptomic Landscape of Human Skin Mast Cells: Unveiling Lineage‐Specific Noncoding RNA Dynamics in FcεRI Activation

BACKGROUND: Mast cells (MCs) are crucial in allergic and inflammatory responses, including in skin disorders. However, the transcriptional landscape of resting and stimulated skin MCs and the role of long non-coding RNAs (lncRNAs) remain poorly characterized. OBJECTIVE: To define FcεRI-induced gene and promoter regulation in primary mast cells from human foreskin (n = 5 cultures) and breast skin (n = 2 cultures), assess tissue-origin effects, identify novel lncRNAs, and evaluate MALAT1 function. METHODS: Skin-derived MCs were stimulated by FcεRI aggregation and subjected to Low Quantity single-strand Cap Analysis of Gene Expression (LQ-ssCAGE) sequencing. MALAT1 knockdown was achieved via antisense oligonucleotides. Functional evaluations included flow cytometry, caspase-3 activity, cytokine secretome studies, and histamine release assays. RESULTS: FcεRI cross-linking induced considerable changes, with over 5000 genes and 6400 promoters being differentially regulated, also encompassing many novel MC-enriched lncRNAs, e.g., CATG00000075668, CATG00000072979, and CATG00000048788. Selected cytokines were among the strongest responders, and their pattern was largely reproduced at the secretome level (e.g., GM-CSF, IL-5, TNF, LIF). Cell surface receptors like NTRK were likewise boosted. Moderate differences were noted between MCs from breast and foreskin, mainly affecting cytokines and tryptase isoenzymes. MALAT1 influenced the transcription of only few genes, but contributed to FcεRI-triggered histamine release. CONCLUSION: FcεRI aggregation triggered widespread transcriptional reprogramming in skin MCs, also encompassing novel MC-selective lncRNAs. The skin source made a modest contribution to FcεRI responsiveness, while MALAT1 fine-tuned MC function. The study shows that lncRNAs can be successfully manipulated in primary tissue MCs to further determine the function of this new class of biomolecules.