A conserved YAP/Notch/REST network controls the neuroendocrine cell fate in the lungs [Hes1 RNA-seq]. A conserved YAP/Notch/REST network controls the neuroendocrine cell fate in the lungs [Hes1 RNA-seq]

The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using heterogeneity in small cell lung cancer as a model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer. Overall design: To determine transcriptomic differences between Hes1-GFP- NE cells and Hes1-GFP+ non-NE cells in mouse small cell lung cancer tumors by bulk RNA-seq. 4 pairs of Hes1-GFP- and Hes1-GFP+ cells sorted from 4 mice.

Notch通路（Notch pathway）是一类高度保守的细胞间通信通路，负责调控细胞命运决定。本研究旨在阐明Notch通路激活如何抑制肺部神经内分泌细胞命运——这是由Notch信号介导的细胞命运决定的经典过程，但其分子机制迄今仍未得到充分解析。我们以小细胞肺癌的异质性作为模型系统，发现转录调控因子REST与YAP可作为神经内分泌向非神经内分泌表型转化的促进因子。我们进一步明确了该过程中，Notch下游的REST所靶向抑制的特异性神经内分泌基因程序。尤为重要的是，我们验证了REST与YAP在肺部发育及组织修复过程中，介导神经内分泌向非神经内分泌细胞命运转换的关键作用。综上，本研究明确了REST与YAP在Notch介导的胚胎肺、成年肺及肺癌中神经内分泌细胞命运抑制过程中的保守调控作用。整体实验设计：通过批量RNA测序（bulk RNA-seq），分析小鼠小细胞肺癌肿瘤中Hes1-GFP阴性（Hes1-GFP⁻）神经内分泌细胞与Hes1-GFP阳性（Hes1-GFP⁺）非神经内分泌细胞之间的转录组差异。本实验共设置4组配对样本，分别从4只小鼠体内分选得到Hes1-GFP⁻与Hes1-GFP⁺细胞。