Genome-wide chromatin analyses of liver cells upon YAP induction [Liver_ChIPSeq_LapTTA]

YAP1 is a transcriptional co-activator regulated by the Hippo pathway, mechano-transduction, G-protein coupled receptors and WNT signaling. YAP1 activity depends on its stabilization and its nuclear localization. Once in the nucleus, YAP1 can regulate gene expression by interacting with transcription factors with DNA binding capability. While YAP1 main transcriptional partners belong to the TEAD family, several reports indicate that YAP1 can also associate with SMADs, RUNX and other transcription factors. YAP1 acts as a broad regulator of cell growth and differentiation, thus playing a pivotal role in regeneration, re-programming and cancer. How YAP1 may control such a large number of cellular processes is still to be fully understood. To identify how YAP1 controls transcription and to define gene expression programs directly regulated by YAP1, we conducted a genome wide investigation in the mouse liver. Integrated analyses of ChIP-seq and RNA-seq data indicated that YAP1 can act both as an activator and as a repressor in a context dependent way, and allowed the dissection of transcriptional mechanisms. Longitudinal analysis by ChIP-seq and RNA-seq highlighted differences in genome binding and transcriptional control which allowed the identification of acute and tonic YAP1 dependent responses. While during acute activation YAP1 supported cell cycle and signal transduction programs, its prolonged activation sustained a feedforward loop that potentiated and expanded YAP1 dependent transcription thus leading to the direct engagement of cell identity programs. Overall this study provides a genome scale understanding of how YAP1 controls gene expression and reveals principles in gene regulation which account for YAP1 ability to orchestrate development, regeneration and cell reprogramming. ChIPseq and ATAC seq analyses were performed on liver of LaptTA-WT (wild type control) or LaptTA-tetYAP mice activated for 4 weeks (4W) Please note that the processed data generated from all replicates is linked to the corresponding 'rep 1' sample records and indicated in the associated sample description field.

YAP1是受Hippo通路、机械转导、G蛋白偶联受体及WNT信号通路调控的转录共激活因子（transcriptional co-activator）。YAP1的活性依赖于其蛋白稳定性与核定位。当其进入细胞核后，可通过与具备DNA结合能力的转录因子相互作用调控基因表达。尽管YAP1的主要转录伙伴隶属于TEAD家族，但多项研究表明，YAP1还可与SMADs、RUNX及其他转录因子结合。YAP1作为细胞生长与分化的广谱调控因子，在机体再生、细胞重编程及癌症发生发展中发挥关键作用。目前，YAP1如何调控如此众多的细胞进程仍未完全阐明。为解析YAP1调控转录的分子机制，并明确YAP1直接调控的基因表达程序，我们在小鼠肝脏中开展了全基因组范围的研究。对染色质免疫共沉淀测序（ChIP-seq，chromatin immunoprecipitation sequencing）与RNA测序（RNA-seq）数据的整合分析显示，YAP1可根据具体情境同时发挥转录激活与抑制的双重作用，并解析了其转录调控机制。通过ChIP-seq与RNA-seq开展的纵向分析，揭示了基因组结合与转录调控模式的差异，进而鉴定出YAP1依赖的急性与持续性应答。在急性激活阶段，YAP1可支持细胞周期与信号转导相关的基因程序；而其长期激活则会维持一个前馈调控环路，该环路可增强并扩大YAP1依赖的转录过程，最终直接激活细胞身份相关的基因程序。总体而言，本研究实现了YAP1调控基因表达机制的全基因组尺度解析，并揭示了基因调控的核心原理，这些原理可解释YAP1协调发育、再生与细胞重编程的能力。本研究对LaptTA-WT（野生型对照）或LaptTA-tetYAP小鼠的肝脏开展了ChIP-seq与转座酶可及性测序（ATAC-seq，Assay for Transposase-Accessible Chromatin using sequencing）分析，两组小鼠分别被诱导激活4周（4W）。请注意，所有重复样本生成的已处理数据均关联至对应的"rep 1"样本记录，并在关联的样本描述字段中予以标注。