Dean Samena, Tang Justin I, Seckl Jonathan R, Nyirenda Moffat J
Endocrinology Unit, Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Gene Expr. 2010;14(6):337-44. doi: 10.3727/105221610x12717040569901.
Hepatocyte nuclear factor 4-alpha (HNF4-alpha) regulates expression of a number of genes in several metabolic organs. The HNF4-alpha gene has two promoters and encodes at least nine isoforms through differential splicing. In mouse liver, transcription initiates at promoter 2 (P2) during fetal life, but switches to P1 at birth. Developmental and tissue-specific expression of HNF4-alpha in other organs is largely unknown. Here, we examined expression of P1- and P2-derived transcripts in a number of mouse and rat tissues. Both P1 and P2 were active in mouse fetal liver, but P2-derived isoforms were detected 50% more abundantly than P1 transcripts. Conversely, the adult mouse liver expressed significantly higher levels of P1- than P2-derived mRNA. In contrast, in the rat, P1 was used more predominantly in both fetal and adult liver. Exposure of fetal rats to the synthetic glucocorticoid dexamethasone caused suppression of P2 while enhancing hepatic expression of transcripts from P1. This was associated with increased expression of erythropoietin and phosphoenolpyruvate carboxykinase, which are key HNF4-alpha targets in the liver. Unlike liver, the kidney and stomach used promoters more selectively, so that only P1-derived isoforms were detected in fetal and adult kidneys in mice or rats, whereas the stomach in both species expressed P2-derived transcripts exclusively. No significant HNF4-alpha mRNA was detected in the spleen. These data reveal striking developmental and tissue-specific variation in expression of HNF4-alpha, and indicate that this can be influenced by environmental factors (such as exposure to glucocorticoid excess), with potential pathophysiological consequences.
肝细胞核因子4α（HNF4α）调节多个代谢器官中许多基因的表达。HNF4α基因有两个启动子，并通过可变剪接编码至少九种异构体。在小鼠肝脏中，胎儿期转录起始于启动子2（P2），但出生时转换为P1。HNF4α在其他器官中的发育和组织特异性表达在很大程度上尚不清楚。在这里，我们检测了多种小鼠和大鼠组织中源自P1和P2的转录本的表达情况。P1和P2在小鼠胎儿肝脏中均有活性，但检测到源自P2的异构体比源自P1的转录本丰富50%。相反，成年小鼠肝脏中源自P1的mRNA表达水平明显高于源自P2的。相比之下，在大鼠中，P1在胎儿和成年肝脏中使用得更为主要。给胎儿大鼠注射合成糖皮质激素地塞米松会导致P2受到抑制，同时增强源自P1的转录本在肝脏中的表达。这与促红细胞生成素和磷酸烯醇丙酮酸羧激酶表达增加有关，它们是肝脏中HNF4α的关键靶点。与肝脏不同，肾脏和胃对启动子的使用更具选择性，因此在小鼠或大鼠的胎儿和成年肾脏中仅检测到源自P1的异构体，而两种物种的胃中仅表达源自P2的转录本。在脾脏中未检测到明显的HNF4α mRNA。这些数据揭示了HNF4α表达在发育和组织特异性方面的显著差异，并表明其可受环境因素（如暴露于糖皮质激素过量）影响，具有潜在的病理生理后果。
