The transcriptional coactivator YAP is emerging as a master regulator of cell growth. In the liver, YAP activity is linked to hepatomegaly, regeneration, dedifferentiation, and aggressive tumor growth. Here we present genomic studies to address how YAP may elicit such profound biological changes in murine models. YAP bound the genome in a TEAD-dependent manner, either at loci constitutively occupied by TEAD or by pioneering enhancers, which comprised a fraction of HNF4a/FOXA-bound embryonic enhancers active during embryonic development but silent in the adult. YAP triggered transcription on promoters by recruiting BRD4, enhancing H3K122 acetylation, and promoting RNApol2 loading and pause-release. YAP also repressed HNF4a target genes by binding to their promoters and enhancers, thus preventing RNApol2 pause-release. YAP activation led to the induction of hepatocyte proliferation, accompanied by tissue remodeling, characterized by polarized macrophages, exhausted T-lymphocytes and dedifferentiation of endothelial cells into proliferative progenitors. Overall, these analyses suggest that YAP is a master regulator of liver function that reshapes the enhancer landscape to control transcription of genes involved in metabolism, proliferation, and inflammation, subverts lineage specification programs by antagonizing HNF4a and modulating the immune infiltrate and the vascular architecture of the liver.

中文翻译：

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解码肝脏中的 YAP 依赖性转录

转录共激活因子 YAP 正在成为细胞生长的主要调节剂。在肝脏中，YAP 活性与肝肿大、再生、去分化和侵袭性肿瘤生长有关。在这里，我们提出了基因组研究，以解决 YAP 如何在小鼠模型中引发如此深刻的生物学变化。YAP 以依赖于 TEAD 的方式结合基因组，无论是在由 TEAD 组成性占据的基因座上，还是在由先驱增强子占据的基因座上，该基因组包含一小部分 HNF4a/FOXA 结合的胚胎增强子，在胚胎发育过程中活跃，但在成人中沉默。YAP 通过招募 BRD4、增强 H3K122 乙酰化和促进 RNApol2 加载和暂停释放来触发启动子的转录。YAP 还通过与其启动子和增强子结合来抑制 HNF4a 靶基因，从而阻止 RNApol2 暂停释放。YAP 激活导致肝细胞增殖的诱导，伴随着组织重塑，其特征是极化巨噬细胞、耗尽的 T 淋巴细胞和内皮细胞去分化为增殖性祖细胞。总体而言，这些分析表明，YAP 是肝功能的主要调节因子，它重塑增强子景观以控制参与代谢、增殖和炎症的基因的转录，通过拮抗 HNF4a 和调节免疫浸润和血管结构来颠覆谱系规范程序。肝脏。