Hippo signaling influences HNF4A and FOXA2 enhancer switching during hepatocyte differentiation.
Hippo signaling influences HNF4A and FOXA2 enhancer switching during hepatocyte differentiation.
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DOI：
10.1016/j.celrep.2014.08.046
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发表时间：
2014-10-09
期刊：
影响因子：
8.8
通讯作者：
Hoodless PA
中科院分区：
文献类型：
--
作者：
Alder O;Cullum R;Lee S;Kan AC;Wei W;Yi Y;Garside VC;Bilenky M;Griffith M;Morrissy AS;Robertson GA;Thiessen N;Zhao Y;Chen Q;Pan D;Jones SJM;Marra MA;Hoodless PA
细胞命运的获得在很大程度上受到主调控因子和组织特异性增强因子之间直接相互作用的影响。然而，通常在祖细胞和成熟细胞群体中表达的谱系指定转录因子如何影响细胞分化仍不清楚。以活体小鼠肝脏发育为模型，我们发现了数千个增强子，它们以分化依赖的方式与主调控因子HNF4A和FOXA2结合，受染色质重塑影响，并与差异表达的靶基因相关。在胚胎中独占的增强子被发现对发育调节的TEAD2和辅激活子YAP1有反应。我们的数据表明，Hippo信号可能通过影响HNF4A和FOXA2与时间增强子的相互作用来影响肝细胞分化。总之，转录因子-增强子相互作用不仅是组织特异性的，而且是分化依赖性的，这是研究癌症生物学或哺乳动物发育和/或使用转化细胞系的研究人员的重要考虑因素。
Cell fate acquisition is heavily influenced by direct interactions between master regulators and tissue-specific enhancers. However, it remains unclear how lineage-specifying transcription factors, which are often expressed in both progenitor and mature cell populations, influence cell differentiation. Using in vivo mouse liver development as a model, we identified thousands of enhancers that are bound by the master regulators HNF4A and FOXA2 in a differentiation-dependent manner, subject to chromatin remodeling, and associated with differentially expressed target genes. Enhancers exclusively occupied in the embryo were found to be responsive to developmentally regulated TEAD2 and coactivator YAP1. Our data suggest that Hippo signaling may affect hepatocyte differentiation by influencing HNF4A and FOXA2 interactions with temporal enhancers. In summary, transcription factor-enhancer interactions are not only tissue specific but also differentiation dependent, which is an important consideration for researchers studying cancer biology or mammalian development and/or using transformed cell lines.