ArticleAmerican journal of physiology. Lung cellular and molecular physiology2016
BRD4 mediates NF-κB-dependent epithelial-mesenchymal transition and pulmonary fibrosis via transcriptional elongation.
Article in American journal of physiology. Lung cellular and molecular physiology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers.
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Who cites it
84 citing papers in PubMed, 113 citations in OpenAlex.
- Disease-specific tau polymorphs are associated with unique protein networks across proteinopathies.The EMBO journal · 2026Article
- Bromodomain-containing protein 4 in inflammatory diseases: molecular mechanisms and therapeutic potential.Journal of inflammation (London, England) · 2026Review
- IRF1 mediates airway epithelial innate memory through priming BRD4- EP300 activity.Frontiers in immunology · 2026Article
- Tubular NAT10 Promotes the Secretion of TGF-β and Lactate to Drive Fibroblast Activation in Diabetic Kidney Disease.International journal of biological sciences · 2026Article
- SLFN14 functions as a P-TEFb inhibitor to modulate the transcription of HIV-1 and cellular genes.Science advances · 2025Article
- BRD2 bromodomain-mediated regulation of cell state plasticity modulates therapy response in glioblastoma.Neuro-oncology · 2025Article
- Computational discovery of BRD4 inhibitors for neuroblastoma therapy using pharmacophore screening and molecular simulations.Scientific reports · 2025Article
- Repurposing flavopiridol as an inhaled therapeutic for pulmonary fibrosis.European journal of pharmacology · 2025Article
- BRD4 Mediates Transforming Growth Factor-β-Induced Smooth Muscle Cell Differentiation from Mesenchymal Progenitor Cells.International journal of molecular sciences · 2025Article
- An orally bioavailable BRD4 inhibitor disrupts expansion of a pathogenic epithelial-mesenchymal niche in bleomycin-induced fibrosis.Respiratory research · 2025Article
- An Elastase Inhibitor ShSPI from Centipede Attenuates Bleomycin-Induced Pulmonary Fibrosis.Toxins · 2025Article
- Orally Bioavailable BRD4 BD1 Inhibitor ZL0516 Effectively Suppresses Colonic Inflammation in Animal Models of Inflammatory Bowel Disease.ACS pharmacology & translational science · 2025Article
- SMARCA4 regulates inducible BRD4 genomic redistribution coupling intrinsic immunity and plasticity in epithelial injury-repair.Nucleic acids research · 2025Article
- Interactions between epithelial mesenchymal plasticity, barrier dysfunction and innate immune pathways shape the genesis of allergic airway disease.Expert review of respiratory medicine · 2025Review
- Immune mechanisms and novel therapies for idiopathic pulmonary fibrosis.Pharmaceutical science advances · 2024Review
- Unlocking the secrets of aging: Epigenetic reader BRD4 as the target to combatting aging-related diseases.Journal of advanced research · 2024Review
- BRD4: an effective target for organ fibrosis.Biomarker research · 2024Review
- A Review of the Bromodomain and Extraterminal Domain Epigenetic Reader Proteins: Function on Virus Infection and Cancer.Viruses · 2024Review
- NF-κB/RelA signaling in secretoglobin progenitors mediates plasticity and MMP-induced barrier disruption in house dust mite-induced allergic asthma.American journal of physiology. Lung cellular and molecular physiology · 2024Article
- Targeting BRD4: Potential therapeutic strategy for head and neck squamous cell carcinoma (Review).Oncology reports · 2024Article
24 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Chronic epithelial injury triggers a TGF-β-mediated cellular transition from normal epithelium into a mesenchymal-like state that produces subepithelial fibrosis and airway remodeling. Here we examined how TGF-β induces the mesenchymal cell state and determined its mechanism. We observed that TGF-β stimulation activates an inflammatory gene program controlled by the NF-κB/RelA signaling pathway. In the mesenchymal state, NF-κB-dependent immediate-early genes accumulate euchromatin marks and processive RNA polymerase. This program of immediate-early genes is activated by enhanced expression, nuclear translocation, and activating phosphorylation of the NF-κB/RelA transcription factor on Ser276, mediated by a paracrine signal. Phospho-Ser276 RelA binds to the BRD4/CDK9 transcriptional elongation complex, activating the paused RNA Pol II by phosphorylation on Ser2 in its carboxy-terminal domain. RelA-initiated transcriptional elongation is required for expression of the core epithelial-mesenchymal transition transcriptional regulators SNAI1, TWIST1, and ZEB1 and mesenchymal genes. Finally, we observed that pharmacological inhibition of BRD4 can attenuate experimental lung fibrosis induced by repetitive TGF-β challenge in a mouse model. These data provide a detailed mechanism for how activated NF-κB and BRD4 control epithelial-mesenchymal transition initiation and transcriptional elongation in model airway epithelial cells in vitro and in a murine pulmonary fibrosis model in vivo. Our data validate BRD4 as an in vivo target for the treatment of pulmonary fibrosis associated with inflammation-coupled remodeling in chronic lung diseases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.