Cited2, a coactivator of HNF4a, is essential for liver development
Cited2, a coactivator of HNF4a, is essential for liver development
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DOI：
10.1038/sj.emboj.7601883
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发表时间：
2007-10-31
期刊：
影响因子：
11.4
通讯作者：
Yang, Yu-Chung
中科院分区：
文献类型：
--
作者：
Qu, Xiaoling;Lam, Eric;Yang, Yu-Chung
转录调控因子Cited2受多种生物刺激的诱导，包括低氧、细胞因子、生长因子、脂多糖和血流剪切。在这项研究中，我们报告了Cited2是小鼠胎肝发育所必需的。Cited2(-/-)胎肝表现为发育不良，细胞凋亡率较高，细胞-细胞接触紊乱，肝窦结构紊乱，脂代谢和肝糖异生受损。此外，我们还展示了Cited2与肝脏富集型转录因子HNF4α之间的物理和功能相互作用。染色质免疫沉淀(ChIP)分析进一步证实了Cited2在HNF4α反应启动子上的募集，以及在没有Cited2的情况下HNF4α与其靶基因启动子的结合减少。综上所述，这项研究表明，缺乏Cited2的小鼠胎肝缺陷至少部分是由于其对HNF4α的共激活功能缺陷造成的。
The transcriptional modulator Cited2 is induced by various biological stimuli including hypoxia, cytokines, growth factors, lipopolysaccharide (LPS) and flow shear. In this study, we report that Cited2 is required for mouse fetal liver development. Cited2(-/-) fetal liver displays hypoplasia with higher incidence of cell apoptosis, and exhibits disrupted cell-cell contact, disorganized sinusoidal architecture, as well as impaired lipid metabolism and hepatic gluconeogenesis. Furthermore, we demonstrated the physical and functional interaction of Cited2 with liver-enriched transcription factor HNF4 alpha. Chromatin immunoprecipitation (ChIP) assays further confirmed the recruitment of Cited2 onto the HNF4 alpha-responsive promoters and the reduced HNF4 alpha binding to its target gene promoters in the absence of Cited2. Taken together, this study suggests that fetal liver defects in mice lacking Cited2 result, at least in part, from its defective coactivation function for HNF4 alpha.