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

ELife
Akela KuwaharaJeffrey O Bush

Abstract

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.

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Citations

Mar 31, 2021·Development·Yongchun ZhangJianwen Que
Apr 12, 2021·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Hirofumi Kiyokawa, Mitsuru Morimoto
May 24, 2021·Developmental Biology·Nicole A EdwardsAaron M Zorn
Dec 2, 2021·American Journal of Physiology. Lung Cellular and Molecular Physiology·Natalia Bottasso-AriasDebora Sinner

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Methods Mentioned

BETA
scRNA-seq
immunoprecipitation
FACS
RNA-seq
ChIP-seq
ChIP
cesarean section
single cell sequencing
dissection
RNAseq

Software Mentioned

FindAllMarkers
bowtie2
Galaxy
RunUMAP
CellRanger
CreateSuratObject
RNAscope
ElbowPlot
RunPCA
Integrative Genomics Viewer

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