Justyna A Karolak1,2, Tomasz Gambin1,3, Przemyslaw Szafranski1, Paweł Stankiewicz4. 1. Department of Molecular & Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm ABBR-R809, Houston, TX, 77030, USA. 2. Chair and Department of Genetics and Pharmaceutical Microbiology, Poznan University of Medical Sciences, 60-781, Poznan, Poland. 3. Institute of Computer Science, Warsaw University of Technology, 00-665, Warsaw, Poland. 4. Department of Molecular & Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm ABBR-R809, Houston, TX, 77030, USA. pawels@bcm.edu.
Abstract
BACKGROUND: The epithelial-mesenchymal signaling involving SHH-FOXF1, TBX4-FGF10, and TBX2 pathways is an essential transcriptional network operating during early lung organogenesis. However, precise regulatory interactions between different genes and proteins in this pathway are incompletely understood. METHODS: To identify TBX2 and TBX4 genome-wide binding sites, we performed chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) in human fetal lung fibroblasts IMR-90. RESULTS: We identified 14,322 and 1,862 sites strongly-enriched for binding of TBX2 and TBX4, respectively, 43.95% and 18.79% of which are located in the gene promoter regions. Gene Ontology, pathway enrichment, and DNA binding motif analyses revealed a number of overrepresented cues and transcription factor binding motifs relevant for lung branching that can be transcriptionally regulated by TBX2 and/or TBX4. In addition, TBX2 and TBX4 binding sites were found enriched around and within FOXF1 and its antisense long noncoding RNA FENDRR, indicating that the TBX4-FGF10 cascade may directly interact with the SHH-FOXF1 signaling. CONCLUSIONS: We highlight the complexity of transcriptional network driven by TBX2 and TBX4 and show that disruption of this crosstalk during morphogenesis can play a substantial role in etiology of lung developmental disorders.
BACKGROUND: The epithelial-mesenchymal signaling involving SHH-FOXF1, TBX4-FGF10, and TBX2 pathways is an essential transcriptional network operating during early lung organogenesis. However, precise regulatory interactions between different genes and proteins in this pathway are incompletely understood. METHODS: To identify TBX2 and TBX4 genome-wide binding sites, we performed chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) in human fetal lung fibroblasts IMR-90. RESULTS: We identified 14,322 and 1,862 sites strongly-enriched for binding of TBX2 and TBX4, respectively, 43.95% and 18.79% of which are located in the gene promoter regions. Gene Ontology, pathway enrichment, and DNA binding motif analyses revealed a number of overrepresented cues and transcription factor binding motifs relevant for lung branching that can be transcriptionally regulated by TBX2 and/or TBX4. In addition, TBX2 and TBX4 binding sites were found enriched around and within FOXF1 and its antisense long noncoding RNA FENDRR, indicating that the TBX4-FGF10 cascade may directly interact with the SHH-FOXF1 signaling. CONCLUSIONS: We highlight the complexity of transcriptional network driven by TBX2 and TBX4 and show that disruption of this crosstalk during morphogenesis can play a substantial role in etiology of lung developmental disorders.
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