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Cell Dev. Biol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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-\u03b21) 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Data on differential DNA-methylation and gene expression were generated from RDEB-KCs following a 4-week exposure to TGF-\u03b21 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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 -\n                      <jats:italic>GPR68<\/jats:italic>\n                      and\n                      <jats:italic>FBLIM1<\/jats:italic>\n                      modulated by TGF-\u03b21, and\n                      <jats:italic>ODF2<\/jats:italic>\n                      responsive to IL-6, as persistently deregulated and demethylated even 4\u00a0weeks after treatment termination, a finding that was further confirmed\n                      <jats:italic>in vitro<\/jats:italic>\n                      . 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcell.2026.1810599","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T04:56:02Z","timestamp":1778129762000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Long-term cytokine exposure remodels the methylome and transcriptome of recessive dystrophic epidermolysis bullosa keratinocytes \u2013 a bioinformatic analysis"],"prefix":"10.3389","volume":"14","author":[{"given":"Julia I.","family":"Hummel","sequence":"first","affiliation":[{"name":"Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg","place":["Salzburg, Austria"]},{"name":"EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg","place":["Salzburg, Austria"]},{"name":"Department of Biosciences and Medical Biology, Paris-Lodron University of Salzburg","place":["Salzburg, Austria"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roland","family":"Zauner","sequence":"additional","affiliation":[{"name":"EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital 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