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TGF?-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression.


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 TGF?-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 TGF?-mediated fibroblast activation. Treatment of lung fibroblasts with pracinostat broadly attenuated TGF?-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 (PGC1?) in response to TGF? 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 TGF?-mediated fibroblast activation via targeted gene repression.

SUBMITTER: Jones DL 

PROVIDER: S-EPMC6826010 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Jones Dakota L DL   Haak Andrew J AJ   Caporarello Nunzia N   Choi Kyoung M KM   Ye Zhenqing Z   Yan Huihuang H   Varelas Xaralabos X   Ordog Tamas T   Ligresti Giovanni G   Tschumperlin Daniel J DJ  

Journal of cell science 20191018 20


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.  ...[more]

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