Delineating the early transcriptional specification of the mammalian trachea and esophagus
Delineating the early transcriptional specification of the mammalian trachea and esophagus
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DOI：
10.7554/elife.55526
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发表时间：
2020-06-09
期刊：
影响因子：
7.7
通讯作者：
Bush, Jeffrey O.
中科院分区：
文献类型：
--
作者：
Kuwahara, Akela;Lewis, Ace E.;Bush, Jeffrey O.
指定哺乳动物气管和食管的基因组规模的转录程序是未知的。虽然NKX 2 -1和SOX 2被假设为气管食管命运的共抑制主调节因子，但这在整个转录组规模上未经测试，并且它们的下游网络仍然未被识别。通过将单细胞RNA测序与Nkx 2 -1突变体的批量RNA测序和小鼠胚胎中的NKX 2 -1 ChIP测序相结合，我们描绘了气管食管特化中的NKX 2 -1转录程序，并发现大多数气管和食管转录组是NKX 2 -1独立的。为了将NKX 2 -1转录程序与SOX 2的调节分离，我们询问了Sox 2/Nkx 2 -1复合突变体中新鉴定的气管和食管标记物的表达。最后，我们发现NKX 2 -1直接与Shh和Wnt 7 b结合，并调节其表达以控制软骨和平滑肌的间充质特化，将上皮身份与间充质特化偶联。这些发现为在全基因组水平上理解早期气管食管命运的规范建立了一个新的框架。
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.