Cited by 77Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisHistone Deacetylase Inhibitors ResearchTGF-β signaling in diseases

TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

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Jones, Dakota L., Haak, Andrew J., Caporarello, Nunzia, Choi, Kyoung M., Ye, Zhenqing, Yan, Huihuang, Varelas, Xaralabos, Ordog, Tamas +2 more·2019·Journal of Cell Science

Abstract

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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Crossref · 10.1242/jcs.233486

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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
Venue
Journal of Cell Science
Published
2019-10-15
Volume
132
Issue
20
ISSN
  • 0021-9533 (ISSN-L)
  • 1477-9137
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
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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