The Hippo Pathway Prevents YAP/TAZ-Driven Hypertranscription and Controls Neural Progenitor Number [RNA-seq]

The Hippo pathway controls the activity of YAP/TAZ transcriptional coactivators through a kinase cascade. Despite the critical role of this pathway in tissue growth and tumorigenesis, it is not fully understood how YAP/TAZ-mediated transcription drives proliferation. By analyzing the effects of inactivating LATS1/2 kinases, the direct upstream inhibitors of YAP/TAZ, on mouse brain development and applying cell-number-normalized transcriptome analysis, we discovered that YAP/TAZ activation causes a global increase in transcription activity, known as hypertranscription, and upregulates many genes associated with increased biosynthetic capacity and proliferation. In contrast, conventional read-depth-normalized RNA-sequencing analysis failed to detect the scope of the transcriptome shift and missed most relevant gene ontologies. Hypertranscription in neural progenitors inhibits differentiation and triggers DNA replication stress, DNA damage, and p53 activation, resulting in massive apoptosis. Our findings reveal the remarkable impact of YAP/TAZ activation on global transcription activity and have important implications for understanding YAP/TAZ function. Cell-number-normalized RNA-seq comparing E12.5 WT and Lats1/2;Nestin-Cre dKO mouse telencephalonsHippo通路（Hippo pathway）通过激酶级联反应调控YAP/TAZ转录共激活因子（YAP/TAZ transcriptional coactivators）的活性。尽管该通路在组织生长与肿瘤发生中发挥关键作用，但YAP/TAZ介导的转录如何驱动细胞增殖的机制尚未完全阐明。本研究通过分析YAP/TAZ的直接上游抑制剂LATS1/2激酶（LATS1/2 kinases）失活对小鼠脑发育的影响，并应用细胞数归一化转录组分析（cell-number-normalized transcriptome analysis），发现YAP/TAZ激活会引发转录活性的全局性升高，即转录亢进（hypertranscription），同时上调大量与增强生物合成能力及细胞增殖相关的基因。与之相反，常规测序读长归一化RNA测序（conventional read-depth-normalized RNA-sequencing）分析无法检测到该转录组变化的整体范围，且遗漏了绝大多数相关的基因本体论（gene ontologies）条目。神经祖细胞中的转录亢进会抑制细胞分化，诱发DNA复制应激、DNA损伤及p53激活，最终导致大规模细胞凋亡。本研究揭示了YAP/TAZ激活对全局转录活性的显著影响，为理解YAP/TAZ的生物学功能提供了重要参考。本数据集为用于对比E12.5野生型（E12.5 WT）与Lats1/2;Nestin-Cre dKO小鼠端脑的细胞数归一化RNA测序数据集。