LncRNA GAS5 suppresses TGF-β1-induced transformation of pulmonary pericytes into myofibroblasts by recruiting KDM5B and promoting H3K4me2/3 demethylation of the PDGFRα/β promoter

Mol Med. 2023 Mar 14;29(1):32. doi: 10.1186/s10020-023-00620-x.

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a condition that may cause persistent pulmonary damage. The transformation of pericytes into myofibroblasts has been recognized as a key player during IPF progression. This study aimed to investigate the functions of lncRNA growth arrest-specific transcript 5 (GAS5) in myofibroblast transformation during IPF progression.

Methods: We created a mouse model of pulmonary fibrosis (PF) via intratracheal administration of bleomycin. Pericytes were challenged with exogenous transforming growth factor-β1 (TGF-β1). To determine the expression of target molecules, we employed quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemical and immunofluorescence staining. The pathological changes in the lungs were evaluated via H&E and Masson staining. Furthermore, the subcellular distribution of GAS5 was examined using FISH. Dual-luciferase reporter assay, ChIP, RNA pull-down, and RIP experiments were conducted to determine the molecular interaction.

Results: GAS5 expression decreased whereas PDGFRα/β expression increased in the lungs of IPF patients and mice with bleomycin-induced PF. The in vitro overexpression of GAS5 or silencing of PDGFRα/β inhibited the TGF-β1-induced differentiation of pericytes to myofibroblasts, as evidenced by the upregulation of pericyte markers NG2 and desmin as well as downregulation of myofibroblast markers α-SMA and collagen I. Further mechanistic analysis revealed that GAS5 recruited KDM5B to promote H3K4me2/3 demethylation, thereby suppressing PDGFRα/β expression. In addition, KDM5B overexpression inhibited pericyte-myofibroblast transformation and counteracted the promotional effect of GAS5 knockdown on pericyte-myofibroblast transformation. Lung fibrosis in mice was attenuated by GAS5 overexpression but promoted by GAS5 deficiency.

Conclusion: GAS5 represses pericyte-myofibroblast transformation by inhibiting PDGFRα/β expression via KDM5B-mediated H3K4me2/3 demethylation in IPF, identifying GAS5 as an intervention target for IPF.

Keywords: GAS5; Idiopathic pulmonary fibrosis; Myofibroblasts; PDGFRα/β.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bleomycin / adverse effects
  • DNA-Binding Proteins / metabolism
  • Demethylation
  • Fibroblasts / metabolism
  • Idiopathic Pulmonary Fibrosis* / chemically induced
  • Idiopathic Pulmonary Fibrosis* / genetics
  • Idiopathic Pulmonary Fibrosis* / metabolism
  • Jumonji Domain-Containing Histone Demethylases / metabolism
  • Lung
  • Mice
  • Mice, Inbred C57BL
  • Myofibroblasts / metabolism
  • Pericytes / metabolism
  • Pericytes / pathology
  • RNA, Long Noncoding* / genetics
  • RNA, Long Noncoding* / metabolism
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Transforming Growth Factor beta1 / metabolism

Substances

  • Bleomycin
  • DNA-Binding Proteins
  • Jumonji Domain-Containing Histone Demethylases
  • Kdm5b protein, mouse
  • Receptor, Platelet-Derived Growth Factor alpha
  • RNA, Long Noncoding
  • Transforming Growth Factor beta1
  • long non-coding RNA GAS5, mouse