PLX235761

GSE136534: TGF-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

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 RNAi-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. SOURCE: Daniel,Rothschild,OBrien (obrien.daniel@mayo.edu) - The Mayo Clinic