Academic Journal
RUNX1 is a mediator of fibrotic activation and epigenetic memory in lung fibroblasts.
| Title: | RUNX1 is a mediator of fibrotic activation and epigenetic memory in lung fibroblasts. |
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| Authors: | Gilbert RM; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States., Jones DL; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States., Wellmerling J; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States., Caporarello N; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States.; Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Chicago, IL, United States., Meridew JA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States., Choi KM; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States., Haak AJ; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States., Link PA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States., Tan Q; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States.; The Hormel Institute, University of Minnesota, Austin, MN, United States., Lee JH; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States., Ordog T; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States., Ligresti G; Department of Medicine, Boston University School of Medicine, Boston, MA, United States., Tschumperlin DJ; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States. |
| Source: | American journal of respiratory cell and molecular biology [Am J Respir Cell Mol Biol] 2026 Jul 01; Vol. 74 (7), pp. 911-923. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: American Thoracic Society Country of Publication: England NLM ID: 8917225 Publication Model: Print Cited Medium: Internet ISSN: 1535-4989 (Electronic) Linking ISSN: 10441549 NLM ISO Abbreviation: Am J Respir Cell Mol Biol Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2000- : New York, NY : American Thoracic Society Original Publication: [New York, NY : The Association, [c1989- |
| MeSH Terms: | Core Binding Factor Alpha 2 Subunit*/metabolism , Core Binding Factor Alpha 2 Subunit*/genetics , Fibroblasts*/metabolism , Fibroblasts*/pathology , Lung*/pathology , Lung*/metabolism , Pulmonary Fibrosis*/pathology , Pulmonary Fibrosis*/genetics , Pulmonary Fibrosis*/metabolism , Epigenesis, Genetic*, Mesoderm/metabolism ; Mesoderm/pathology ; Mesenchymal Stem Cells/metabolism ; Animals ; Epigenetic Memory ; Mice ; Mice, Inbred C57BL ; Fibrosis ; Cells, Cultured |
| Abstract: | Repetitive injury is hypothesized to lead to progressive tissue fibrosis and end-stage organ failure. Whether tissue-resident mesenchymal cell populations retain epigenetic memory of prior injuries that contribute to this pathological process is unknown. Here we used a genetic lineage labeling approach to mark the lung mesenchyme prior to injury, then performed multimodal analyses on isolated lung mesenchyme during the initiation, progression, and resolution of the fibrotic response. Our results demonstrate the remarkable epigenetic and transcriptional plasticity of the lung mesenchyme during fibrotic activation and de-activation. Despite this plasticity, we also find that the lung mesenchyme exhibits an enhanced fibrotic program upon reinjury. We identify RUNX1 as a critical driver of both fibrotic activation and fibrotic memory. Comparison of fresh isolated and cultured lung mesenchyme demonstrates that RUNX1 is spontaneously activated in standard culture conditions, previously masking these roles of RUNX1. Targeted knockdown of RUNX1 dampens fibrotic mesenchymal cell activation immediately after cell isolation, but with reduced efficacy after only days of culture, confirming its functional importance to both early activation and long-term memory. Collectively, our findings implicate RUNX1 in the initiation and memory of fibrotic mesenchymal cell activation that together prime enhanced mesenchymal cell responses upon repeated injury. (© The Author(s) 2026. Published by Oxford University Press on behalf of the American Thoracic Society.) |
| Comments: | Comment in: Am J Respir Cell Mol Biol. 2026 Jul 1;74(7):832-834. doi: 10.1093/ajrcmb/aanag055.. (PMID: 42089297) |
| Grant Information: | F32 HL175907 United States HL NHLBI NIH HHS; R01 HL153026 United States HL NHLBI NIH HHS; R01 HL166187 United States HL NHLBI NIH HHS; HL166187 United States NH NIH HHS; HL175907 United States NH NIH HHS; HL173656 United States NH NIH HHS; HL142596 United States NH NIH HHS; DK84567 United States NH NIH HHS; DAALA2023-1045091 American Lung Association; Boehringer Ingelheim ILD-Discovery |
| Contributed Indexing: | Keywords: ATACseq; ChIPseq; RNAseq; lung fibrosis; multi-omics |
| Substance Nomenclature: | 0 (Core Binding Factor Alpha 2 Subunit) 0 (Runx1 protein, mouse) |
| Entry Date(s): | Date Created: 20260225 Date Completed: 20260630 Latest Revision: 20260726 |
| Update Code: | 20260726 |
| PubMed Central ID: | PMC13316937 |
| DOI: | 10.1093/ajrcmb/aanag022 |
| PMID: | 41738205 |
| Database: | MEDLINE |
| ISSN: | 1535-4989 |
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| DOI: | 10.1093/ajrcmb/aanag022 |