Identification of Potential Pathogenic Super-Enhancers-Driven Genes in Pulmonary Fibrosis

Li, Hang; Zhao, Caiping; Li, Zeli; Yao, Kainan; Zhang, Jingjing; Si, Wenwen; Liu, Xiaohong; Jiang, Yong; Zhu, Meiling

doi:10.3389/fgene.2021.644143

Cited by 6 publications

(5 citation statements)

References 31 publications

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“…Pulmonary fibrosis caused by injury and infection is typically one of the chronic, prolonged pulmonary disease processes, along with excessive deposition of the ECM ( 118 , 119 ). Moreover, multiple cytokines (including IFN-γ, TGF-β, IL-1β, TNF-α, IL-8 etc.)…”

Section: Grk2 and Fibrotic Diseasementioning

confidence: 99%

G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases

Shan

et al. 2022

Front. Immunol.

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G protein-coupled receptor kinase 2 (GRK2), an important subtype of GRKs, specifically phosphorylates agonist-activated G protein-coupled receptors (GPCRs). Besides, current research confirms that it participates in multiple regulation of diverse cells via a non-phosphorylated pathway, including interacting with various non-receptor substrates and binding partners. Fibrosis is a common pathophysiological phenomenon in the repair process of many tissues due to various pathogenic factors such as inflammation, injury, drugs, etc. The characteristics of fibrosis are the activation of fibroblasts leading to myofibroblast proliferation and differentiation, subsequent aggerate excessive deposition of extracellular matrix (ECM). Then, a positive feedback loop is occurred between tissue stiffness caused by ECM and fibroblasts, ultimately resulting in distortion of organ architecture and function. At present, GRK2, which has been described as a multifunctional protein, regulates copious signaling pathways under pathophysiological conditions correlated with fibrotic diseases. Along with GRK2-mediated regulation, there are diverse effects on the growth and apoptosis of different cells, inflammatory response and deposition of ECM, which are essential in organ fibrosis progression. This review is to highlight the relationship between GRK2 and fibrotic diseases based on recent research. It is becoming more convincing that GRK2 could be considered as a potential therapeutic target in many fibrotic diseases.

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Section: Grk2 and Fibrotic Diseasementioning

confidence: 99%

G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases

Shan

et al. 2022

Front. Immunol.

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“…Moreover, serum LTBP2 was also elevated in patients with COVID-19-related PF. Consistently, Li et al (Li et al, 2021) demonstrated that LTBP2 was highly expressed in lungs of mice with PF. More importantly, we found that LTBP2 silencing by lentiviral transfection attenuated BLM-induced PF in mice.…”

Section: Discussionmentioning

confidence: 56%

“…While NF-κB is a key signaling pathway targeted by LTBP2 in PF, we cannot rule out the involvement of other signaling pathways which would be very interesting to explore in future studies. In addition, although LTBP2 has not been reported to have transcription factor-like functions, a previous study showed that LTBP2 was one of the super-enhancer-driven pathogenic genes in lung fibrosis and Myc was one of the transcription factors binding to the LTBP2 superenhancer (Li et al, 2021). Therefore, it's not ruled out that LTBP2 may directly regulate promoter activity of α-SMA, fibronectin and Col1α, and it would be necessary to explore in the future.…”

Section: Discussionmentioning

confidence: 99%

Latent Transforming Growth Factor-β Binding Protein-2 Regulates Lung Fibroblast-to-Myofibroblast Differentiation in Pulmonary Fibrosis via NF-κB Signaling

Zou

et al. 2021

Front. Pharmacol.

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Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. The aberrantly activated lung myofibroblasts, predominantly emerging through fibroblast-to-myofibroblast differentiation, are considered to be the key cells in PF, resulting in excessive accumulation of extracellular matrix (ECM). Latent transforming growth factor-β (TGFβ) binding protein-2 (LTBP2) has been suggested as playing a critical role in modulating the structural integrity of the ECM. However, its function in PF remains unclear. Here, we demonstrated that lungs originating from different types of patients with PF, including idiopathic PF and rheumatoid arthritis-associated interstitial lung disease, and from mice following bleomycin (BLM)-induced PF were characterized by increased LTBP2 expression in activated lung fibroblasts/myofibroblasts. Moreover, serum LTBP2 was also elevated in patients with COVID-19-related PF. LTBP2 silencing by lentiviral shRNA transfection protected against BLM-induced PF and suppressed fibroblast-to-myofibroblast differentiation in vivo and in vitro. More importantly, LTBP2 overexpression was able to induce differentiation of lung fibroblasts to myofibroblasts in vitro, even in the absence of TGFβ1. By further mechanistic analysis, we demonstrated that LTBP2 silencing prevented fibroblast-to-myofibroblast differentiation and subsequent PF by suppressing the phosphorylation and nuclear translocation of NF-κB signaling. LTBP2 overexpression-induced fibroblast-to-myofibroblast differentiation depended on the activation of NF-κB signaling in vitro. Therefore, our data indicate that intervention to silence LTBP2 may represent a promising therapy for PF.

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“…The function of super-enhancers is reflected by their associated genes ( Li et al, 2021a ). KEGG pathway gene enrichment analysis is helpful to find out the possible roles of these super-enhancer–associated genes in the development and progression of IBD.…”

Section: Discussionmentioning

confidence: 99%

“…Enhancers, DNA sequences on the genome, precisely regulate the spatiotemporal expression of target genes through cis-interactions during cell development and differentiation ( Witte et al, 2015 ; Li et al, 2021a ). It is an important cis-regulatory element in the cell identity and the development process of multicellular organisms ( Agrawal and Rao, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Nintedanib Alleviates Experimental Colitis by Inhibiting CEBPB/PCK1 and CEBPB/EFNA1 Pathways

et al. 2022

Front. Pharmacol.

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The super-enhancer, a cluster of enhancers with strong transcriptional activity, has become one of the most interesting topics in recent years. This study aimed to investigate pathogenic super-enhancer–driven genes in IBD and screen therapeutic drugs based on the results. In this study, through the analysis of differentially expressed genes in colitis patients from the GEO database and the analysis of the super-enhancer–associated database, we found that the super-enhancer pathogenic genes PCK1 and EFNA1 were simultaneously regulated by transcription factor CEBPB through two super-enhancers (sc-CHR20-57528535 and sc-CHR1-155093980). Silencing CEBPB could significantly inhibit the expression of PCK1 and EFNA1 and enhance the expression of epithelial barrier proteins claudin-1, occludin, and ZO-1. In LPS-induced Caco-2 cells, drugs commonly used in clinical colitis including tofacitinib, oxalazine, mesalazine, and sulfasalazine inhibited mRNA levels of CEBPB, PCK1, and EFNA1. In the drug screening, we found that nintedanib significantly inhibited the mRNA and protein levels of CEBPB, PCK1, and EFNA1. In vivo experiments, nintedanib significantly alleviated DSS-induced colitis in mice by inhibiting CEBPB/PCK1 and CEBPB/EFNA1 signaling pathways. At the genus level, nintedanib improved the composition of the gut microbiota in mice with DSS-induced experimental colitis. In conclusion, we found that PCK1 and EFNA1 are highly expressed in colitis and they are regulated by CEBPB through two super-enhancers, and we further demonstrate their role in vivo and in vitro. Nintedanib may be a potential treatment for IBD. Super-enhancers may be a new way to explore the pathogenesis of colitis.

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Identification of Potential Pathogenic Super-Enhancers-Driven Genes in Pulmonary Fibrosis

Cited by 6 publications

References 31 publications

G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases

G Protein-Coupled Receptor Kinase 2 as Novel Therapeutic Target in Fibrotic Diseases

Latent Transforming Growth Factor-β Binding Protein-2 Regulates Lung Fibroblast-to-Myofibroblast Differentiation in Pulmonary Fibrosis via NF-κB Signaling

Nintedanib Alleviates Experimental Colitis by Inhibiting CEBPB/PCK1 and CEBPB/EFNA1 Pathways

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