Potential interactions between the TBX4-FGF10 and SHH-FOXF1 signaling during human lung development revealed using ChIP-seq

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.

First Genotype–Phenotype Study in TBX4 Syndrome: Gain-of-Function Mutations Causative for Lung Disease

“…Our reporter system was designed using the standard T-BOX motif and FGF10 promoter sequences. A recent report of TBX4 chromatin immunoprecipitation in human fetal lung fibroblasts identified several other potential genome-wide target sites whose effects we have not tested ( 39 ). Therefore, a variant shown to have a modest or benign effect by our luciferase assay may still have significant damaging effects on interactions with other crucial binding sites in biologically relevant tissues.…”

First genotype-phenotype study in TBX4 syndrome: gain-of-function mutations causative for lung disease

“…Our reporter system was designed using the standard T-BOX motif and FGF10 promoter sequences. A recent report of TBX4 chromatin immunoprecipitation in human fetal lung fibroblasts identified several other potential genome-wide target sites whose effects we have not tested (38).…”

“…Our reporter system was designed using the standard T-BOX motif and FGF10 promoter sequences. A recent report of TBX4 chromatin immunoprecipitation in human fetal lung fibroblasts identified several other potential genome-wide target sites whose effects we have not tested (38). Therefore, a variant shown to have a modest or benign effect by our luciferase assay may still have significant damaging effects on interactions with other crucial binding sites in biologically relevant tissues.…”

Gene expression profiles in mesenchymal stromal cells from bone marrow, adipose tissue and lung tissue of COPD patients and controls

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