JUNB O‐GlcNAcylation‐Mediated Promoter Accessibility of Metabolic Genes Modulates Distinct Epithelial Lineage in Pulmonary Fibrosis
Abstract Idiopathic pulmonary fibrosis (IPF) is a lethal disease with substantial unmet medical needs. While aberrant epithelial remodeling is a key factor in IPF progression, the molecular mechanisms behind this process remain elusive. Harnessing a 3D patient‐derived organoid model and multi‐omics...
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202406751 |
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| author | Marie‐Therese Bammert Meshal Ansari Leoni Haag Zuhdi Ahmad Victoria Schröder Joseph Birch Diana Santacruz Werner Rust Coralie Viollet Benjamin Strobel Alec Dick Florian Gantner Holger Schlüter Fidel Ramirez Muriel Lizé Matthew J. Thomas Huy Q. Le |
| author_facet | Marie‐Therese Bammert Meshal Ansari Leoni Haag Zuhdi Ahmad Victoria Schröder Joseph Birch Diana Santacruz Werner Rust Coralie Viollet Benjamin Strobel Alec Dick Florian Gantner Holger Schlüter Fidel Ramirez Muriel Lizé Matthew J. Thomas Huy Q. Le |
| author_sort | Marie‐Therese Bammert |
| collection | DOAJ |
| description | Abstract Idiopathic pulmonary fibrosis (IPF) is a lethal disease with substantial unmet medical needs. While aberrant epithelial remodeling is a key factor in IPF progression, the molecular mechanisms behind this process remain elusive. Harnessing a 3D patient‐derived organoid model and multi‐omics approach, the first inventory of the connection between metabolic alteration, chromatin accessibility, and transcriptional regulation in IPF aberrant epithelial remodeling is provided. This remodeling is characterized by an increase in chromatin accessibility, particularly at JUNB motif‐enriched promoter regions proximal to transcription start sites of metabolic and pro‐fibrotic genes. Mechanistically, JUNB undergoes O‐linked β‐N‐acetylglucosamine modification (O‐GlcNAcylation), a critical step in modulating pro‐fibrotic responses to chronic injury. This modification is pivotal in fostering the emergence of aberrant epithelial basal cells in the alveolar niche, a proposed driver of IPF pathology. Specific deletion of O‐GlcNAcylation sites on JUNB attenuates the metaplastic differentiation of basal cells, thereby aiding in the restoration of the alveolar lineage. Together, the findings reveal a novel link between metabolic dysregulation and cell fate regulation at the chromatin level in fibrosis, mediated by the O‐GlcNAc‐JUNB axis, suggesting avenues for the development of new therapeutic strategies in IPF. |
| format | Article |
| id | doaj-art-37847580cdfd4528a626cd6a2c19c46d |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-37847580cdfd4528a626cd6a2c19c46d2025-02-04T13:14:54ZengWileyAdvanced Science2198-38442025-02-01125n/an/a10.1002/advs.202406751JUNB O‐GlcNAcylation‐Mediated Promoter Accessibility of Metabolic Genes Modulates Distinct Epithelial Lineage in Pulmonary FibrosisMarie‐Therese Bammert0Meshal Ansari1Leoni Haag2Zuhdi Ahmad3Victoria Schröder4Joseph Birch5Diana Santacruz6Werner Rust7Coralie Viollet8Benjamin Strobel9Alec Dick10Florian Gantner11Holger Schlüter12Fidel Ramirez13Muriel Lizé14Matthew J. Thomas15Huy Q. Le16Lung Repair & Regeneration Department Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyGlobal Computational Biology and Digital Science Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyLung Repair & Regeneration Department Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyLung Repair & Regeneration Department Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyLung Repair & Regeneration Department Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyLung Repair & Regeneration Department Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyGlobal Computational Biology and Digital Science Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyGlobal Computational Biology and Digital Science Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyGlobal Computational Biology and Digital Science Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyDrug Discovery Sciences Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyGlobal Computational Biology and Digital Science Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyFaculty of Biology University of Konstanz 78457 Konstanz GermanyLung Repair & Regeneration Department Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyGlobal Computational Biology and Digital Science Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyLung Repair & Regeneration Department Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyLung Repair & Regeneration Department Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyLung Repair & Regeneration Department Boehringer Ingelheim Pharma GmbH & Co. KG 88400 Biberach GermanyAbstract Idiopathic pulmonary fibrosis (IPF) is a lethal disease with substantial unmet medical needs. While aberrant epithelial remodeling is a key factor in IPF progression, the molecular mechanisms behind this process remain elusive. Harnessing a 3D patient‐derived organoid model and multi‐omics approach, the first inventory of the connection between metabolic alteration, chromatin accessibility, and transcriptional regulation in IPF aberrant epithelial remodeling is provided. This remodeling is characterized by an increase in chromatin accessibility, particularly at JUNB motif‐enriched promoter regions proximal to transcription start sites of metabolic and pro‐fibrotic genes. Mechanistically, JUNB undergoes O‐linked β‐N‐acetylglucosamine modification (O‐GlcNAcylation), a critical step in modulating pro‐fibrotic responses to chronic injury. This modification is pivotal in fostering the emergence of aberrant epithelial basal cells in the alveolar niche, a proposed driver of IPF pathology. Specific deletion of O‐GlcNAcylation sites on JUNB attenuates the metaplastic differentiation of basal cells, thereby aiding in the restoration of the alveolar lineage. Together, the findings reveal a novel link between metabolic dysregulation and cell fate regulation at the chromatin level in fibrosis, mediated by the O‐GlcNAc‐JUNB axis, suggesting avenues for the development of new therapeutic strategies in IPF.https://doi.org/10.1002/advs.202406751aberrant epithelial remodelingbronchiolizationJUNBO‐GlcNAcylationpulmonary fibrosis |
| spellingShingle | Marie‐Therese Bammert Meshal Ansari Leoni Haag Zuhdi Ahmad Victoria Schröder Joseph Birch Diana Santacruz Werner Rust Coralie Viollet Benjamin Strobel Alec Dick Florian Gantner Holger Schlüter Fidel Ramirez Muriel Lizé Matthew J. Thomas Huy Q. Le JUNB O‐GlcNAcylation‐Mediated Promoter Accessibility of Metabolic Genes Modulates Distinct Epithelial Lineage in Pulmonary Fibrosis Advanced Science aberrant epithelial remodeling bronchiolization JUNB O‐GlcNAcylation pulmonary fibrosis |
| title | JUNB O‐GlcNAcylation‐Mediated Promoter Accessibility of Metabolic Genes Modulates Distinct Epithelial Lineage in Pulmonary Fibrosis |
| title_full | JUNB O‐GlcNAcylation‐Mediated Promoter Accessibility of Metabolic Genes Modulates Distinct Epithelial Lineage in Pulmonary Fibrosis |
| title_fullStr | JUNB O‐GlcNAcylation‐Mediated Promoter Accessibility of Metabolic Genes Modulates Distinct Epithelial Lineage in Pulmonary Fibrosis |
| title_full_unstemmed | JUNB O‐GlcNAcylation‐Mediated Promoter Accessibility of Metabolic Genes Modulates Distinct Epithelial Lineage in Pulmonary Fibrosis |
| title_short | JUNB O‐GlcNAcylation‐Mediated Promoter Accessibility of Metabolic Genes Modulates Distinct Epithelial Lineage in Pulmonary Fibrosis |
| title_sort | junb o glcnacylation mediated promoter accessibility of metabolic genes modulates distinct epithelial lineage in pulmonary fibrosis |
| topic | aberrant epithelial remodeling bronchiolization JUNB O‐GlcNAcylation pulmonary fibrosis |
| url | https://doi.org/10.1002/advs.202406751 |
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