A systematic analysis of the 3'UTR of HNF4A mRNA reveals an interplay of regulatory elements including miRNA target sites.
A systematic analysis of the 3'UTR of HNF4A mRNA reveals an interplay of regulatory elements including miRNA target sites.
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DOI：
10.1371/journal.pone.0027438
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Ryffel GU
中科院分区：
文献类型：
--
作者：
Wirsing A;Senkel S;Klein-Hitpass L;Ryffel GU
肝细胞核因子4α（hepatocyte nuclear factor 4α，HNF 4 α）功能障碍与青年成熟型糖尿病（maturity onset diabetes of young，MODY 1）、II型糖尿病及肾细胞癌（renal cell carcinoma，RCC）有关。虽然引起糖尿病的突变是众所周知的，但在RCC中没有发现HNF 4A突变。由于迄今为止的分析仅限于HNF 4A的启动子和开放阅读框架，因此我们对人HNF 4A的3′UTR进行了系统分析。我们在HEK 293和INS-1细胞中鉴定了一个短的（1724 nt）和长的（3180 nt）3′UTR，它们比开放阅读框架长得多，并在荧光素酶报告基因测定中赋予了抑制作用。通过将3′UTR分成几段，我们定位了两个约400 nt的不同元件，它们赋予了高度的抑制作用。这些负性元件A和B被位于HNF 4A 3′UTR 5′端的39 nt的平衡元件抵消。Dicer敲除实验表明HNF 4A 3′UTR受miRNA调控。更详细的分析表明，miR-34 a和miR-21在RCC中均过表达，协同下调HNF 4A mRNA。其中一个识别的miR-34 a结合位点被SNP rs 11574744破坏。HNF 4 α 3′UTR内几个调控元件的鉴定证明了分析3′UTR序列以探索HNF 4 α在糖尿病和RCC中的功能障碍是合理的。
Dysfunction of hepatocyte nuclear factor 4α (HNF4α) has been linked to maturity onset diabetes of the young (MODY1), diabetes type II and possibly to renal cell carcinoma (RCC). Whereas diabetes causing mutations are well known, there are no HNF4A mutations found in RCC. Since so far analyses have been constricted to the promoter and open reading frame of HNF4A, we performed a systematic analysis of the human HNF4A 3′UTR. We identified a short (1724 nt) and long (3180 nt) 3′UTR that are much longer than the open reading frame and conferred a repressive effect in luciferase reporter assays in HEK293 and INS-1 cells. By dissecting the 3′UTR into several pieces, we located two distinct elements of about 400 nt conferring a highly repressive effect. These negative elements A and B are counteracted by a balancer element of 39 nt located within the 5′ end of the HNF4A 3′UTR. Dicer knock-down experiments implied that the HNF4A 3′UTR is regulated by miRNAs. More detailed analysis showed that miR-34a and miR-21 both overexpressed in RCC cooperate in downregulation of the HNF4A mRNA. One of the identified miR-34a binding sites is destroyed by SNP rs11574744. The identification of several regulatory elements within the HNF4A 3′UTR justifies the analysis of the 3′UTR sequence to explore the dysfunction of HNF4α in diabetes and RCC.
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