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.
Original language | English |
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Article number | 2406751 |
Journal | Advanced Science |
Volume | 12 |
Issue number | 5 |
Early online date | 15 Dec 2024 |
DOIs | |
Publication status | Published - 3 Feb 2025 |
Data Availability Statement
ATAC- and RNA-seq data generated within this study was deposited in theGene Expression Omnibus and will be made accessible upon acceptance
of the manuscript. All other data is available on request.
Acknowledgements
The authors thank A. Arduini for critical reading of the manuscript, D. Jonigk and the German Centre for Lung Research (DZL/BREATH) Hannover for providing patient-derived lung tissue, I. Kollak, E. Peter, J. Hill, D. Schäfer, L. Beck, N. Rehm, C. Mayr, J. Hoffmann, S. Klee, L. Di Niro, R. Ammann, B. Lämmle, and the Drug Discovery Sciences department for technical assistance and support.Funding
This work was funded by Boehringer Ingelheim Pharma GmbH und Co. KG. All drawings were created using Biorender.com.
Keywords
- aberrant epithelial remodeling
- bronchiolization
- JUNB
- O-GlcNAcylation
- pulmonary fibrosis
ASJC Scopus subject areas
- Medicine (miscellaneous)
- General Chemical Engineering
- General Materials Science
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
- General Engineering
- General Physics and Astronomy