TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression
Open accessAbstract
Tissue fibrosis is a chronic disease driven by persistent fibroblast activation that has recently been linked to epigenetic modifications. Here, we screened a small library of epigenetic small-molecule modulators to identify compounds capable of inhibiting or reversing TGFβ-mediated fibroblast activation. We identified pracinostat, an HDAC inhibitor, as a potent attenuator of lung fibroblast activation and confirmed its efficacy in patient-derived fibroblasts isolated from fibrotic lung tissue. Mechanistically, we found that HDAC-dependent transcriptional repression was an early and essential event in TGFβ-mediated fibroblast activation. Treatment of lung fibroblasts with pracinostat broadly attenuated TGFβ-mediated epigenetic repression and promoted fibroblast quiescence. We confirmed a specific role for HDAC-dependent histone deacetylation in the promoter region of the anti-fibrotic gene PPARGC1A (PGC1α) in response to TGFβ stimulation. Finally, we identified HDAC7 as a key factor whose siRNA-mediated knockdown attenuates fibroblast activation without altering global histone acetylation. Together, these results provide novel mechanistic insight into the essential role HDACs play in TGFβ-mediated fibroblast activation via targeted gene repression.
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Persistent TGF-β signaling drives sustained fibroblast activation.
“Persistent TGF-β signaling drives sustained fibroblast activation [15]”
From Ensemble of Time-Evolving SASP Gene Sets Identifies IGFBP7 and CDKN1A as a Potential Marker Pair for Senescent Fibroblast Subpopulations Across Tissues (2026) · cites this paper as [15]
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Self-citation
- Authors
- Jones, D. L., Haak, A. J., Caporarello, N., Choi, K. M., Ye, Z., Yan, H., Varelas, X., Ordog, T., Ligresti, G., & Tschumperlin, D. J.
- Affiliations
- Mayo Clinic (US)
- Boston University (US)
- Mayo Clinic 1 Department of Physiology & Biomedical Engineering , , Rochester, MN 55905, USA
- ORCID
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2019-10-15
- Volume
- 132
- Issue
- 20
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- PMC
- PMC6826010
- OpenAlex
- W2974610252
- Cited by
- 77
- References
- 99
- Citations by year
- 2026: 12 · 2025: 10 · 2024: 15 · 2023: 9 · 2022: 10 · 2021: 13 · 2020: 7 · 2018: 1
- FWCI
- 5.52
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health (HL105355, HL142596, HL092961, HL133320)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- TGF-beta signaling, fibroblast activation, fibrosis, histone deacetylase inhibitors, pracinostat, HDAC7, histone deacetylation, epigenetic gene repression, PGC-1α, lung fibroblasts, antifibrotic therapy
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Cell Line, Fibroblasts, Histone Deacetylases, Humans, Lung, Promoter Regions, Genetic, Pulmonary Fibrosis, Down-Regulation, Transforming Growth Factor beta
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