1. Academic Validation
  2. 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

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.
Yichun Wang # 1 Diyu Chen # 2 Han Xie 3 Shuhua Zhou 3 Mingwang Jia 4 Xiaobo He 4 Feifei Guo 4 Yihuan Lai 4 Xiao Xiao Tang 5
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, No. 63 Duobao Road, Liwan District, Guangzhou, 510150, Guangdong Province, People's Republic of China. wangyichun2005@sina.com.
  • 2 CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510150, Guangdong Province, People's Republic of China.
  • 3 Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China.
  • 4 Department of Critical Care Medicine, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, No. 63 Duobao Road, Liwan District, Guangzhou, 510150, Guangdong Province, People's Republic of China.
  • 5 State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, No. 195 Dongfeng West Road, Yuexiu District, Guangzhou, 510150, Guangdong Province, People's Republic of China. tangxiaoxiao@gird.cn.
  • # Contributed equally.
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.

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