RRC ID 62056
Author Horie M, Miyashita N, Mikami Y, Noguchi S, Yamauchi Y, Suzukawa M, Fukami T, Ohta K, Asano Y, Sato S, Yamaguchi Y, Ohshima M, Suzuki HI, Saito A, Nagase T.
Title TBX4 is involved in the super-enhancer-driven transcriptional programs underlying features specific to lung fibroblasts.
Journal Am J Physiol Lung Cell Mol Physiol
Abstract Lung fibroblasts participate in the pathogenesis of respiratory diseases, including lung cancer and pulmonary fibrosis. Although fibroblasts are ubiquitous constituents of various organs, their cellular diversity among different organs has been poorly characterized. Here, we aimed to investigate the distinct gene signature of lung fibroblasts that represents its pulmonary origin and the underlying gene regulatory networks. Promoter-level differential expression analysis by cap analysis of gene expression (CAGE) sequencing revealed distinct gene expression patterns of fibroblasts derived from different anatomical sites and identified 88 coding genes with higher expression in lung fibroblasts relative to other fibroblasts. Multiple key transcription factors important for lung mesenchyme development, including the T-box transcription factors TBX2, TBX4, and TBX5 were enriched in this lung-specific signature and were associated with super-enhancers. TBX4 showed highly specific expression in lung fibroblasts and was required for cell proliferation and collagen gel contraction capacity. Transcriptome analysis revealed that TBX4 could broadly regulate fibroblast-related pathways and partly contribute to super-enhancer-mediated transcriptional programs. Of pathological importance, lung fibroblast-specific genes were globally downregulated in lung cancer-associated fibroblasts (CAFs). Notably, TBX2, TBX4, and TBX5 were downregulated and hypermethylated in lung CAFs, suggesting an association between epigenetic silencing of these factors and phenotypic alteration of lung fibroblasts in cancer. Our study highlights the importance of T-box transcription factors, especially TBX4, and super-enhancers in the roles of lung fibroblasts in pulmonary physiology and pathogenesis.
Volume 314(1)
Pages L177-L191
Published 2018-1-1
DOI 10.1152/ajplung.00193.2017
PII ajplung.00193.2017
PMID 28971975
MeSH Biomarkers / metabolism* Cells, Cultured Fibroblasts / cytology Fibroblasts / metabolism* Gene Expression Profiling Gene Expression Regulation, Developmental* Humans Lung / cytology Lung / metabolism* Regulatory Sequences, Nucleic Acid T-Box Domain Proteins / genetics T-Box Domain Proteins / metabolism* Transcription Factors / genetics Transcription Factors / metabolism Transcription, Genetic
IF 4.418
Human and Animal Cells NB1RGB(RCB0222)