JUNB O-GlcNAcylation-mediated promoter accessibility of metabolic genes modulates distinct epithelial lineage in pulmonary fibrosis

Thomas, M. J.; Bammert, M.-T.; Ansari, M.; Haag, L.; Ahmad, Z.; Schroeder, V.; Birch, J.; Santacruz, D.; Rust, W.; Viollet, C.; Strobel, B.; Dick, A.; Gantner, F.; Schleuter, H.; Ramirez, F.; Lize, M.; Le, H. Q.

doi:10.1101/2024.05.27.594700

bioRxiv · 10.1101/2024.05.27.594700

JUNB O-GlcNAcylation-mediated promoter accessibility of metabolic genes modulates distinct epithelial lineage in pulmonary fibrosis

Thomas, M. J.·Bammert, M.-T.·Ansari, M.·Haag, L.·Ahmad, Z.·Schroeder, V.·Birch, J.·Santacruz, D.·Rust, W.·Viollet, C.·Strobel, B.·Dick, A.·Gantner, F.·Schleuter, H.·Ramirez, F.·Lize, M.·Le, H. Q.

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a lethal disease with substantial unmet medical needs. While aberrant epithelial remodelling is a key factor in IPF progression, the molecular mechanisms behind this process remain elusive. Using a patient-derived 3D distal airway epithelial organoid model, we successfully recapitulate important IPF features, including the emergence of aberrant KRT5+/COL1A1+ basal cells and a metabolic shift towards increased O-linked {beta}-N-acetylglucosamine (O-GlcNAc) levels. Consistent with this, single-cell analysis of accessible chromatin reveals an increased chromatin accessibility in these aberrant basal cells, particularly at JUNB motif-enriched promoter regions of metabolic genes. O-GlcNAcylation shapes JUNB function and promotes a pro-fibrotic response to chronic injury, leading to aberrant epithelial remodelling. Site-specific deletion of O-GlcNAcylation on JUNB attenuates the metaplastic differentiation of basal cells, thereby aiding in the restoration of the alveolar lineage. Together, these data establish a novel link between metabolic dysregulation, mediated by the O-GlcNAc-JUNB axis, and bronchiolization in IPF, offering new therapeutic strategies to treat this fatal disease.

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Thomas, M. J., Bammert, M.-T., Ansari, M., Haag, L., Ahmad, Z., Schroeder, V., Birch, J., Santacruz, D., Rust, W., Viollet, C., Strobel, B., Dick, A., Gantner, F., Schleuter, H., Ramirez, F., Lize, M., Le, H. Q.. 2024-05-30. JUNB O-GlcNAcylation-mediated promoter accessibility of metabolic genes modulates distinct epithelial lineage in pulmonary fibrosis. https://doi.org/10.1101/2024.05.27.594700

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