Journal article
CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation during lung fibrosis
JCI insight, Vol.4(12), 127111
06/20/2019
DOI: 10.1172/jci.insight.127111
PMCID: PMC6629126
PMID: 31095524
Abstract
Pulmonary fibrosis is a devastating disease characterized by accumulation of activated fibroblasts and scarring in the lung. While fibroblast activation in physiological wound repair reverses spontaneously, fibroblast activation in fibrosis is aberrantly sustained. Here we identified histone 3 lysine 9 methylation (H3K9me) as a critical epigenetic modification that sustains fibroblast activation by repressing the transcription of genes essential to returning lung fibroblasts to an inactive state. We show that the histone methyltransferase G9a (EHMT2) and chromobox homolog 5 (CBX5, also known as HP1 alpha), which deposit H3K9me marks and assemble an associated repressor complex, respectively, are essential to initiation and maintenance of fibroblast activation specifically through epigenetic repression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha gene (PPARGC1A, encoding PGC1 alpha). Both TGF-beta and increased matrix stiffness potently inhibit PGC1a expression in lung fibroblasts through engagement of the CBX5/G9a pathway. Inhibition of the CBX5/G9a pathway in fibroblasts elevates PGC1 alpha, attenuates TGF-beta- and matrix stiffness-promoted H3K9 methylation, and reduces collagen accumulation in the lungs following bleomycin injury. Our results demonstrate that epigenetic silencing mediated by H3K9 methylation is essential for both biochemical and biomechanical fibroblast activation and that targeting this epigenetic pathway may provide therapeutic benefit by returning lung fibroblasts to quiescence.
Details
- Title: Subtitle
- CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation during lung fibrosis
- Creators
- Giovanni Ligresti - Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN 55905 USANunzia Caporarello - Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN 55905 USAJeffrey A. Meridew - Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN 55905 USADakota L. Jones - Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN 55905 USAQi Tan - Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN 55905 USAKyoung Moo Choi - Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN 55905 USAAndrew J. Haak - Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN 55905 USAAja Aravamudhan - Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN 55905 USAAnja C. Roden - Mayo Clin, Lab Med & Pathol, Rochester, MN 55905 USAY S Prakash - Mayo ClinicGwen Lomberk - Medical College of WisconsinRaul A. Urrutia - Medical College of WisconsinDaniel J. Tschumperlin - Mayo Clin, Dept Physiol & Biomed Engn, Rochester, MN 55905 USA
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.4(12), 127111
- DOI
- 10.1172/jci.insight.127111
- PMID
- 31095524
- PMCID
- PMC6629126
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- Amer Soc Clinical Investigation Inc
- Number of pages
- 21
- Grant note
- HL142596; HL092961; HL133320 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 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)
- Language
- English
- Date published
- 06/20/2019
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9984949237402771
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