A CD44/Brg1 nuclear complex confers mesenchymal progenitor cells with enhanced fibrogenicity in idiopathic pulmonary fibrosis

Yang, Libang; Xia, Hong; Smith, Karen; Gilbertsen, Adam; Beisang, Daniel; Kuo, Jen-Tsai; Bitterman, Peter B.; Henke, Craig A.

doi:10.1172/jci.insight.144652

Cited by 16 publications

(22 citation statements)

References 52 publications

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Section: Discussionsupporting

confidence: 87%

“…There were also studies demonstrating that ZEB1 could achieve its regulatory function by recruiting the chromatin remodelling factor BRG1 in intestinal tumour cells. In addition, the CD44/Brg1/Zeb1 nuclear protein complex was found to target the Sox2 gene and promote its upregulation in fibrogenic mesenchymal progenitor cells (Yang et al., 2021), and similar results have been reported in a previous study showing that ZEB1 represses E‐cadherin and induces EMT by recruiting BRG1 during tumour invasion (Sánchez‐Tilló et al., 2010). These data presented herein suggest that ZEB1 might be the TF recruiting BRG1.…”

Section: Discussionsupporting

confidence: 76%

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ZEB1 recruits BRG1 to regulate airway remodelling epithelial‐to‐mesenchymal transition in asthma

Wang

Peng

Luo

et al. 2022

Experimental Physiology

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New Findings What is the central question of this study?The aim was to investigate the function of brahma‐related gene‐1 (BRG1) in airway remodelling epithelial‐to‐mesenchymal transition (EMT) of asthma and identify the transcription factor of BRG1 that binds to the protomer of E‐cadherin. What is the main finding and its importance?This study highlighted an important molecular mechanism involving chromatin remodelling factor BRG1 that played a crucial role in airway remodelling EMT of asthma and demonstrated that ZEB1 was the key transcription factor recruiting BRG1. This finding might offer new insights into gene‐based therapy for asthma. Abstract Epithelial‐to‐mesenchymal transition (EMT) of airway remodelling happens in children with asthma. A reduction in the epithelial marker E‐cadherin is reported to be one of the initiating factors of EMT. Our previous study showed that chromatin remodelling factor brahma‐related gene‐1 (BRG1) could regulate the expression of E‐cadherin indirectly. However, the transcription factor involved in the recruitment of BRG1 in asthma is unknown. Here, we studied the function of Brg1 in an ovalbumin‐induced asthma model [lung‐specific conditional Brg1 knockdown (Brg1−/−) mice] and human bronchial epithelial 16HBE cells stably expressing BRG1 short hairpin RNA. Our results showed that Brg1 was involved in EMT in asthmatic mice by detecting the expression of EMT markers. We also identified that BRG1 participated in the transforming growth factor‐β‐induced EMT of 16HBE cells. We observed that zinc finger E‐box binding homeobox 1 (ZEB1) and BRG1 co‐localized in the EMT of TGF‐β‐induced 16HBE cells. Further results revealed that ZEB1 recruited BRG1 and bound to the promoter region (+3563/3715) to regulate E‐cadherin expression. Thus, ZEB1 might be the key transcription factor to recruit BRG1 in airway remodelling EMT of asthma and might be a new therapeutic target.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 76%

ZEB1 recruits BRG1 to regulate airway remodelling epithelial‐to‐mesenchymal transition in asthma

Wang

Peng

Luo

et al. 2022

Experimental Physiology

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“…Brahma-related gene 1 (BRG1), encoded by the SMARCA4 gene, is a core catalytic ATPase subunit of the SWItch/Sucrose Non-Fermentable chromatin remodelling complex, which performs fundamental roles in gene regulation and cell lineage specification by altering chromatin structure using energy from ATP hydrolysis [ 26 , 27 ]. Yang et al uncovered that BRG1 interaction with CD44 endows mesenchymal progenitor cells with cell-autonomous fibrogenicity, and conveys them to fibroblastic focus in idiopathic pulmonary fibrosis (IPF), thus drives the progression of IPF [ 28 ]. The fibrogenic role of BRG1 in liver has also been proved by genetic ablation of BRG1 in hepatic progenitor cell, which strongly suppressed liver fibrosis [ 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/β-catenin/autophagy axis

et al. 2021

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Although accelerated cellular senescence is closely related to the progression of chronic kidney disease (CKD) and renal fibrosis, the underlying mechanisms remain largely unknown. Here, we reported that tubular aberrant expression of Brahma-related gene 1 (BRG1), an enzymatic subunit of the SWltch/Sucrose Non-Fermentable complex, is critically involved in tubular senescence and renal fibrosis. BRG1 was significantly upregulated in the kidneys, predominantly in tubular epithelial cells, of both CKD patients and unilateral ureteral obstruction (UUO) mice. In vivo, shRNA-mediated knockdown of BRG1 significantly ameliorated renal fibrosis, improved tubular senescence, and inhibited UUO-induced activation of Wnt/β-catenin pathway. In mouse tubular epithelial cells (mTECs) and primary renal tubular cells, inhibition of BRG1 diminished TGF-β1-induced cellular senescence and fibrotic responses. Correspondingly, ectopic expression of BRG1 in mTECs cells or normal kidneys increased p16INK4a, p19ARF and p21 expression and senescence-associated β-galactosidase activity, indicating accelerated tubular senescence. Additionally, BRG1-mediated pro-fibrotic responses were largely abolished by siRNA-mediated p16INK4a silencing in vitro or continuous senolytic treatment with ABT- 263 in vivo. Moreover, BRG1 activated the Wnt/β-catenin pathway, which further inhibited autophagy. Pharmacologic inhibition of the Wnt/β-catenin pathway (ICG-001) or rapamycin-mediated activation of autophagy effectively blocked BRG1-induced tubular senescence and fibrotic responses, while bafilomycin A1-mediated inhibition of autophagy abolished the effects of ICG-001. Further, BRG1 altered the secretome of senescent tubular cells, which promoted proliferation and activation of fibroblasts. Taken together, our results indicate that BRG1 induces tubular senescence by inhibiting autophagy via the Wnt/β-catenin pathway, which ultimately contributes to the development of renal fibrosis.

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“…These cells were identified as the cell-of-origin for fibroblasts comprising the fibrotic reticulum in IPF. Indeed, gene and protein expression profiling of IPF lung mesenchymal progenitors distinguished them from control lung MPCs, with an enrichment of genes associated with disease-relevant ontologies [129][130][131]. These cells are enriched for pro-fibrotic and senescence factors and exhibit a global loss of transcripts encoding for components of various DNA damage response and repair proteins, including DNA-PKcs [130].…”

Section: Mesenchymal Progenitor Cells (Mpcs)mentioning

confidence: 99%

Cellular Senescence: Pathogenic Mechanisms in Lung Fibrosis

Parimon

Hohmann

Yao

2021

IJMS

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Pulmonary fibrosis is a chronic and fatal lung disease that significantly impacts the aging population globally. To date, anti-fibrotic, immunosuppressive, and other adjunct therapy demonstrate limited efficacies. Advancing our understanding of the pathogenic mechanisms of lung fibrosis will provide a future path for the cure. Cellular senescence has gained substantial interest in recent decades due to the increased incidence of fibroproliferative lung diseases in the older age group. Furthermore, the pathologic state of cellular senescence that includes maladaptive tissue repair, decreased regeneration, and chronic inflammation resembles key features of progressive lung fibrosis. This review describes regulatory pathways of cellular senescence and discusses the current knowledge on the senescence of critical cellular players of lung fibrosis, including epithelial cells (alveolar type 2 cells, basal cells, etc.), fibroblasts, and immune cells, their phenotypic changes, and the cellular and molecular mechanisms by which these cells contribute to the pathogenesis of pulmonary fibrosis. A few challenges in the field include establishing appropriate in vivo experimental models and identifying senescence-targeted signaling molecules and specific therapies to target senescent cells, known collectively as “senolytic” or “senotherapeutic” agents.

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A CD44/Brg1 nuclear complex confers mesenchymal progenitor cells with enhanced fibrogenicity in idiopathic pulmonary fibrosis

Cited by 16 publications

References 52 publications

ZEB1 recruits BRG1 to regulate airway remodelling epithelial‐to‐mesenchymal transition in asthma

ZEB1 recruits BRG1 to regulate airway remodelling epithelial‐to‐mesenchymal transition in asthma

Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/β-catenin/autophagy axis

Cellular Senescence: Pathogenic Mechanisms in Lung Fibrosis

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