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Delineating the early transcriptional specification of the mammalian trachea and esophagus.

Akela KuwaharaAce E LewisCoohleen CoombesFang-Shiuan LeungMichelle PerchardeJeffrey O Bush
Published in: eLife (2020)
The genome-scale transcriptional programs that specify the mammalian trachea and esophagus are unknown. Though NKX2-1 and SOX2 are hypothesized to be co-repressive master regulators of tracheoesophageal fates, this is untested at a whole transcriptomic scale and their downstream networks remain unidentified. By combining single-cell RNA-sequencing with bulk RNA-sequencing of Nkx2-1 mutants and NKX2-1 ChIP-sequencing in mouse embryos, we delineate the NKX2-1 transcriptional program in tracheoesophageal specification, and discover that the majority of the tracheal and esophageal transcriptome is NKX2-1 independent. To decouple the NKX2-1 transcriptional program from regulation by SOX2, we interrogate the expression of newly-identified tracheal and esophageal markers in Sox2/Nkx2-1 compound mutants. Finally, we discover that NKX2-1 binds directly to Shh and Wnt7b and regulates their expression to control mesenchymal specification to cartilage and smooth muscle, coupling epithelial identity with mesenchymal specification. These findings create a new framework for understanding early tracheoesophageal fate specification at the genome-wide level.
Keyphrases
  • single cell
  • transcription factor
  • stem cells
  • rna seq
  • genome wide
  • gene expression
  • smooth muscle
  • cell fate
  • high throughput
  • poor prognosis
  • bone marrow
  • public health
  • heat shock
  • dna methylation
  • long non coding rna