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We determined whether current smoking and COPD are associated with methylation-linked regulatory programs in airway basal cells that shape epithelial differentiation in patient-derived bronchial organoids.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We integrated DNA methylation profiling and bulk transcriptomics in patient-derived airway basal cells and matched three-dimensional bronchial organoids. Methylation-defined gene sets were mapped to organoid epithelial cell states using single-cell RNA-seq and contextualized with publicly available airway epithelial datasets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      In this exploratory cohort, current smoking was associated with a predominant shift toward promoter hypomethylation in airway basal cells and matched organoids. Hypomethylated promoters were enriched for genes preferentially expressed in secretory epithelial cells, including\n                      <jats:italic>BPIFB1<\/jats:italic>\n                      ,\n                      <jats:italic>BPIFA2<\/jats:italic>\n                      ,\n                      <jats:italic>MSMB<\/jats:italic>\n                      and\n                      <jats:italic>GALNT6<\/jats:italic>\n                      . These genes showed little smoking-associated expression difference in basal-cell culture but were upregulated after organoid differentiation, indicating a differentiation-dependent epithelial memory of smoking. In COPD-derived basal cells, promoter methylation changes involved reduced xenobiotic metabolism and enhanced immune- and infection-related programs. Consistently, COPD-derived organoids showed reduced expression of detoxification-associated pathways and increased lysosomal, endocytic and host-defense programs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Current smoking and COPD are associated with persistent methylation-linked regulatory alterations in airway basal cells that become functionally apparent during epithelial differentiation. These findings support a model in which airway basal-cell memory contributes to secretory, inflammatory and host-defense remodeling in chronic airway disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12931-026-03847-4","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T13:43:56Z","timestamp":1788011036000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Current smoking and COPD are associated with differentiation-dependent secretory and inflammatory programs in airway basal cells"],"prefix":"10.1186","volume":"27","author":[{"given":"Felix","family":"Ritzmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Brand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles","family":"Gasparoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Langer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Herr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwen","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Migdat","family":"Mustafi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Yildiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rn","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Bals","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Beisswenger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,29]]},"reference":[{"key":"3847_CR1","doi-asserted-by":"crossref","unstructured":"Jones RL, Noble PB, Elliot JG, James AL. 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