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对 HNF4A mRNA 的 3'UTR 的系统分析揭示了包括 miRNA 靶位在内的调节元件的相互作用。

A systematic analysis of the 3'UTR of HNF4A mRNA reveals an interplay of regulatory elements including miRNA target sites.

机构信息

Institut für Zellbiologie (Tumorforschung), Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.

出版信息

PLoS One. 2011;6(11):e27438. doi: 10.1371/journal.pone.0027438. Epub 2011 Nov 30.

DOI:10.1371/journal.pone.0027438
PMID:22140441
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3227676/
Abstract

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.

摘要

肝细胞核因子 4α (HNF4α) 的功能障碍与青年发病的成年型糖尿病 (MODY1)、2 型糖尿病以及可能与肾细胞癌 (RCC) 有关。虽然导致糖尿病的突变是众所周知的，但在 RCC 中并未发现 HNF4A 突变。由于迄今为止的分析仅限于 HNF4A 的启动子和开放阅读框，我们对人类 HNF4A 3'UTR 进行了系统分析。我们鉴定了一个短 (1724 nt) 和长 (3180 nt) 的 3'UTR，其长度远远超过开放阅读框，并在 HEK293 和 INS-1 细胞中的荧光素酶报告基因测定中表现出抑制作用。通过将 3'UTR 分割成几个片段，我们定位了两个约 400 nt 的独特元件，赋予高度抑制作用。这些负性元件 A 和 B 被位于 HNF4A 3'UTR 5'端的 39 nt 平衡元件抵消。Dicer 敲低实验表明 HNF4A 3'UTR 受 miRNAs 调节。更详细的分析表明，在 RCC 中高表达的 miR-34a 和 miR-21 协同下调 HNF4A mRNA。鉴定出的 miR-34a 结合位点之一被 SNP rs11574744 破坏。在 HNF4A 3'UTR 内发现的几个调节元件证明了对 3'UTR 序列进行分析以探索 HNF4α 在糖尿病和 RCC 中的功能障碍是合理的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/1b503e4d3ddf/pone.0027438.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/10ce257659ec/pone.0027438.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/7c63b0cd2302/pone.0027438.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/1772eae2a3b3/pone.0027438.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/d9fd85630f15/pone.0027438.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/1ea2d0de4ed5/pone.0027438.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/6ffa7f297b23/pone.0027438.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/23e9e13f2c04/pone.0027438.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/4a263c58f823/pone.0027438.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/1b503e4d3ddf/pone.0027438.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/10ce257659ec/pone.0027438.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/7c63b0cd2302/pone.0027438.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/1772eae2a3b3/pone.0027438.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/d9fd85630f15/pone.0027438.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/1ea2d0de4ed5/pone.0027438.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/6ffa7f297b23/pone.0027438.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/23e9e13f2c04/pone.0027438.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/4a263c58f823/pone.0027438.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3a73/3227676/1b503e4d3ddf/pone.0027438.g009.jpg

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