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

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 We used microarrays to compare the gene expression profiles of cortices from control and Lats1F/F;Lats2F/F;Nestin-Cre double knock-out E12.5 mouse embryos.Hippo通路（Hippo pathway）通过激酶级联反应调控YAP/TAZ转录共激活因子的活性。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仍未完全阐明。通过分析YAP/TAZ的直接上游抑制因子——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）方法，我们发现YAP/TAZ激活会引发转录活性的整体上调，即所谓的转录亢进（hypertranscription），同时上调众多与生物合成能力增强及细胞增殖相关的基因。相较之下，传统的基于测序读长归一化的RNA测序（RNA-sequencing）分析无法检测到转录组变化的整体规模，且遗漏了绝大多数相关基因本体论（gene ontologies）条目。神经祖细胞中的转录亢进会抑制细胞分化，并引发DNA复制应激、DNA损伤及p53激活，最终导致大量细胞凋亡。本研究揭示了YAP/TAZ激活对全局转录活性的显著影响，其研究结果对于理解YAP/TAZ的功能具有重要意义。我们使用微阵列技术（microarrays）对比了对照组与Lats1F/F;Lats2F/F;Nestin-Cre双基因敲除（double knock-out）E12.5小鼠胚胎皮层的基因表达谱。