a systematic analysis of the 3′utr of hnf4a mrna reveals an interplay of regulatory elements including mirna target sites系统分析的3u2032utr hnf4a mrna揭示监管元素的相互作用包括microrna的目标网站.pdfVIP

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a systematic analysis of the 3′utr of hnf4a mrna reveals an interplay of regulatory elements including mirna target sites系统分析的3u2032utr hnf4a mrna揭示监管元素的相互作用包括microrna的目标网站.pdf

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a systematic analysis of the 3′utr of hnf4a mrna reveals an interplay of regulatory elements including mirna target sites系统分析的3u2032utr hnf4a mrna揭示监管元素的相互作用包括microrna的目标网站

A Systematic Analysis of the 39UTR of HNF4A mRNA Reveals an Interplay of Regulatory Elements Including miRNA Target Sites ¤ Andrea Wirsing , Sabine Senkel, Ludger Klein-Hitpass, Gerhart U. Ryffel* ¨ ¨ ¨ Institut fur Zellbiologie (Tumorforschung), Universitatsklinikum Essen, Universitat Duisburg-Essen, Essen, Germany Abstract Dysfunction of hepatocyte nuclear factor 4a (HNF4a) 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 39UTR. We identified a short (1724 nt) and long (3180 nt) 39UTR 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 39UTR 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 59 end of the HNF4A 39UTR. Dicer knock-down experiments implied that the HNF4A 39UTR 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 r The identification of several regulatory elements within the HNF4A 39UTR justifies the analysis of the 39UTR sequence to explore the dysfunction of HNF4a in diabetes and RCC. Citation: Wirsing A, Senkel S, Klein-Hitpass L, Ryffel GU (2011) A Systematic Analysis of the 3 9UTR of HN