The stable repression of mesenchymal program is required for hepatocyte identity: a novel role for hepatocyte nuclear factor 4α.
The stable repression of mesenchymal program is required for hepatocyte identity: a novel role for hepatocyte nuclear factor 4α.
复制标题
DOI：
10.1002/hep.24280
复制
发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Tripodi M
中科院分区：
文献类型：
--
作者：
Santangelo L;Marchetti A;Cicchini C;Conigliaro A;Conti B;Mancone C;Bonzo JA;Gonzalez FJ;Alonzi T;Amicone L;Tripodi M
细胞终末分化在发育完成后稳定维持的概念受到了大量观察结果的质疑，这些观察结果表明，分化的上皮可能经历了上皮-间质转化（EMT）过程。EMT和相反的间充质-上皮转化（MET）是发育、组织修复和肿瘤进展的典型事件。在这项研究中，我们旨在阐明肝细胞中这些表型转化的分子机制。肝细胞核因子4α (HNF4α)在不同肝细胞系中过表达，并通过实时定量聚合酶链反应测定其基因表达谱。采用电泳迁移量转移法和染色质免疫沉淀法测定了HNF4α在间充质和EMT调节基因启动子上的募集。在沉默细胞和HNF4敲除动物的全肝中评估了HNF4α缺失的影响。我们的研究结果确定了关键的EMT调节因子和间充质基因是HNF4α的新靶点。HNF4α与其靶蛋白HNF1α合作，直接抑制EMT主调控基因Snail、Slug和HMGA2以及几种间充质标记物的转录。hnf4 α-介导的EMT基因抑制在肝癌中诱导MET，其沉默在细胞培养和全肝中触发分化肝细胞的间充质程序。HNF4α在诱导和维持肝细胞分化中的关键作用也应归因于其持续抑制间充质程序的能力；因此，HNF4α激活因子和抑制因子的功能对于肝细胞的识别是必需的。
The concept that cellular terminal differentiation is stably maintained once development is complete has been questioned by numerous observations showing that differentiated epithelium may undergo an epithelial-to-mesenchymal transition (EMT) program. EMT and the reverse process, mesenchymal-to-epithelial transition (MET), are typical events of development, tissue repair, and tumor progression. In this study, we aimed to clarify the molecular mechanisms underlying these phenotypic conversions in hepatocytes. Hepatocyte nuclear factor 4α (HNF4α) was overexpressed in different hepatocyte cell lines and the resulting gene expression profile was determined by real-time quantitative polymerase chain reaction. HNF4α recruitment on promoters of both mesenchymal and EMT regulator genes was determined by way of electrophoretic mobility shift assay and chromatin immunoprecipitation. The effect of HNF4α depletion was assessed in silenced cells and in the context of the whole liver of HNF4 knockout animals. Our results identified key EMT regulators and mesenchymal genes as new targets of HNF4α. HNF4α, in cooperation with its target HNF1α, directly inhibits transcription of the EMT master regulatory genes Snail, Slug, and HMGA2 and of several mesenchymal markers. HNF4α-mediated repression of EMT genes induces MET in hepatomas, and its silencing triggers the mesenchymal program in differentiated hepatocytes both in cell culture and in the whole liver. The pivotal role of HNF4α in the induction and maintenance of hepatocyte differentiation should also be ascribed to its capacity to continuously repress the mesenchymal program; thus, both HNF4α activator and repressor functions are necessary for the identity of hepatocytes.
登录
查看更多内容
影响因子：
5.3
作者：
Hayhurst, GP;Lee, YH;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
影响因子：
21.3
作者：
Batlle, E;Sancho, E;de Herreros, AG
通讯作者：
de Herreros, AG
影响因子：
4.8
作者：
Kaimori, Aki;Potter, James;Koteish, Ayman
通讯作者：
Koteish, Ayman
影响因子：
3.7
作者：
Satohisa, S;Chiba, H;Sawada, N
通讯作者：
Sawada, N
DOI：
10.1152/ajpgi.00431.2005
发表时间：
2006-03-01
影响因子：
4.5
作者：
Rowley, CW;Staloch, LJ;Simon, TC
通讯作者：
Simon, TC