CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation during lung fibrosis

JCI Insight. 2019 May 16;5(12):e127111. doi: 10.1172/jci.insight.127111.

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 HP1α), 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 PGC1α). Both TGFβ and increased matrix stiffness potently inhibit PGC1α expression in lung fibroblasts through engagement of the CBX5/G9a pathway. Inhibition of CBX5/G9a pathway in fibroblasts elevates PGC1α, attenuates TGFβ- 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.

Keywords: Cell Biology; Epigenetics; Fibrosis; Pulmonology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / toxicity
  • Bleomycin / toxicity
  • Chromobox Protein Homolog 5
  • Chromosomal Proteins, Non-Histone / genetics*
  • Chromosomal Proteins, Non-Histone / metabolism
  • Collagen / metabolism
  • Disease Models, Animal
  • Epigenesis, Genetic
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Gene Silencing
  • Histocompatibility Antigens / genetics*
  • Histocompatibility Antigens / metabolism
  • Histone Code / genetics
  • Histone-Lysine N-Methyltransferase / genetics*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Idiopathic Pulmonary Fibrosis / genetics*
  • Idiopathic Pulmonary Fibrosis / metabolism
  • Idiopathic Pulmonary Fibrosis / pathology
  • Lung / cytology
  • Lung / metabolism*
  • Lung / pathology
  • Mice
  • Mice, Transgenic
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / genetics*
  • Transforming Growth Factor beta / metabolism

Substances

  • Antibiotics, Antineoplastic
  • CBX5 protein, human
  • CBX5 protein, mouse
  • Chromosomal Proteins, Non-Histone
  • Histocompatibility Antigens
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Transforming Growth Factor beta
  • Chromobox Protein Homolog 5
  • Bleomycin
  • Collagen
  • EHMT2 protein, human
  • G9a protein, mouse
  • Histone-Lysine N-Methyltransferase