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

Dakota L. Jones, Andrew J. Haak, Nunzia Caporarello, Kyoung M. Choi, Zhenqing Ye, Huihuang Yan, Xaralabos Varelas, Tamas Ordog, Giovanni Ligresti, Daniel J. Tschumperlin

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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.

Original languageEnglish (US)
Article numberjcs233486
JournalJournal of cell science
Volume132
Issue number20
DOIs
StatePublished - 2019

Keywords

  • Chromatin
  • Epigenetics
  • Fibrosis
  • Myofibroblasts

ASJC Scopus subject areas

  • Cell Biology

Fingerprint Dive into the research topics of 'TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression'. Together they form a unique fingerprint.

Cite this