Journal article
TGF beta-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression
Journal of cell science, Vol.132(20), 233486
10/18/2019
DOI: 10.1242/jcs.233486
PMCID: PMC6826010
PMID: 31527052
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 beta-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 beta-mediated fibroblast activation. Treatment of lung fibroblasts with pracinostat broadly attenuated TGF beta-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 alpha) in response to TGF beta 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 beta-mediated fibroblast activation via targeted gene repression.
Details
- Title: Subtitle
- TGF beta-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression
- Creators
- Dakota L. Jones - Mayo ClinicAndrew J. Haak - Mayo ClinicNunzia Caporarello - Mayo ClinicKyoung M. Choi - Mayo ClinicZhenqing Ye - Mayo Clinic in FloridaHuihuang Yan - Mayo Clinic in FloridaXaralabos Varelas - Boston UniversityTamas Ordog - Mayo ClinicGiovanni Ligresti - Mayo ClinicDaniel J. Tschumperlin - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- Journal of cell science, Vol.132(20), 233486
- DOI
- 10.1242/jcs.233486
- PMID
- 31527052
- PMCID
- PMC6826010
- NLM abbreviation
- J Cell Sci
- ISSN
- 0021-9533
- eISSN
- 1477-9137
- Publisher
- Company Biologists Ltd
- Number of pages
- 14
- Grant note
- T32HL105355 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) American Lung Association HL105355; HL142596; HL092961; HL133320 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 10/18/2019
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9984949238902771
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