Forschung & Innovation
Publikationen
Long-term cytokine exposure remodels the methylome and transcriptome of recessive dystrophic epidermolysis bullosa keratinocytes - a bioinformatic analysis
PMU Autor*innen
Julia I. Hummel, Roland Zauner, Stefanie Gruner, Sonja Dorfer, Michael Ablinger, Caterina Barone, Martin Laimer, Christina Guttmann-Gruber, Josefina Pinon Hofbauer, Ulrich Koller, Johann W. Bauer, Verena Wally
Alle Autor*innen
Julia I. Hummel, Roland Zauner, Stefanie Gruner, Sonja Dorfer, Michael Ablinger, Vanessa Walch, Caterina Barone, Martin Laimer, Christina Guttmann-Gruber, Josefina Pinon Hofbauer, Ulrich Koller, Johann W. Bauer, Verena Wally
Fachzeitschrift
Frontiers in Cell and Developmental Biology
Kurzfassung
Background Recessive dystrophic epidermolysis bullosa (RDEB) is a monogenic skin disorder characterized by severe skin fragility and pronounced clinical variability, even among individuals sharing identical genotypes. Transforming growth factor beta 1 (TGF-beta 1) and Interleukin-6 (IL-6) signaling have previously been linked to disease severity, but the molecular changes of long-term exposure of patient keratinocytes (KCs) - especially at the level of DNA methylation and gene expression - remain relatively unexplored.Methods Data on differential DNA-methylation and gene expression were generated from RDEB-KCs following a 4-week exposure to TGF-beta 1 or IL-6, as well as after an additional 4-week period without treatment, using the EPIC array and RNA-sequencing, respectively. Cytokine induced epigenetic and transcriptional alterations upon treatment and such that remained stable upon treatment withdrawal were identified using bioinformatic tools based on R/Bioconductor packages for data integration and analysis.Results Bioinformatic analysis demonstrated that prolonged cytokine exposure, reflecting chronic inflammation, induced predominantly reversible but also a subset of long-lasting transcriptomic changes in RDEB-KCs. Notably, pathways associated with the RDEB disease phenotype were enriched, with focal adhesion and p53 signaling among the stably altered pathways. Integration of transcriptomic and methylome data identified three genes - GPR68 and FBLIM1 modulated by TGF-beta 1, and ODF2 responsive to IL-6, as persistently deregulated and demethylated even 4 weeks after treatment termination, a finding that was further confirmed in vitro. Moreover, their significant deregulation in RDEB-tumor tissue compared to RDEB-skin controls suggests that cytokine exposure may induce a stable, pro-tumorigenic shift in RDEB-KCs.Conclusion Overall, our bioinformatic results highlight stable cytokine-driven molecular alterations in RDEB-KCs that may contribute to disease pathogenesis and potentially revealed candidate pathways and genes for future mechanistic and therapeutic investigation.
Keywords
KERATINOCYTES, DNA METHYLATION, Recessive dystrophic epidermolysis bullosa, Chronic inflammation, Transcriptome, Epigenetic reprogramming, Pro-tumorigenic shift