The role of microRNAs in hepatocyte nuclear factor-4alpha expression and transactivation.
The role of microRNAs in hepatocyte nuclear factor-4alpha expression and transactivation.
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DOI：
10.1016/j.bbagrm.2012.12.009
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发表时间：
2013-05
影响因子：
4.7
通讯作者：
Burke, Peter A.
中科院分区：
文献类型：
--
作者：
Wang, Zhongyan;Burke, Peter A.
肝细胞核因子（hepatocyte nuclear factor，HNF）-4α是调控肝细胞分化和功能的转录因子网络的关键成员。遗传和分子证据表明HNF-4α的表达主要在转录水平上受到调控。HNF-4A基因的激活涉及增强子和启动子区域内不同转录因子和共转录因子的相互作用。本文研究了microRNA（miRNA）对HNF-4A mRNA 3′-非翻译区（3′-UTR）的抑制作用。利用生物信息学分析鉴定了一组miRNAs的潜在识别元件。miR-34和miR-449的家族成员，包括miR-34 a、miR-34 c-5 p和miR-449 a，共享位于HNF-4A的3′-UTR内的两个不同位置的相同靶元件。miR-34 a、miR-34 c-5 p或miR-449 a在HepG 2细胞中的过表达导致携带HNF-4A 3′-UTR的荧光素酶报告基因活性显著降低。当3′-UTR中缺失一个或两个miR-34 a/miR-34 c-5 p/miR-449 a的结合位点时，对报告基因活性的抑制作用部分或完全消除。miR-34 a、miR-34 c-5 p和miR-449 a的过表达显著降低了HNF-4α的蛋白水平，这与HNF-4α结合活性的降低和HNF-4α靶基因的反式激活相关。这些结果表明HNF-4A的3′-UTR内的miR-34 a、miR-34 c-5 p和miR-449 a的识别位点是功能性的。miRNA下调HNF-4α结合活性和反式激活的机制涉及通过选择性靶向HNF-4A 3 '-UTR的miRNA降低HNF-4α蛋白水平，导致HNF-4α表达的翻译抑制。
Hepatocyte nuclear factor (HNF)-4α is a key member of the transcription factor network regulating hepatocyte differentiation and function. Genetic and molecular evidence suggests that expression of HNF-4α is mainly regulated at the transcriptional level. Activation of HNF-4A gene involves the interaction of distinct sets of transcription factors and co-transcription factors within enhancer and promoter regions. Here we study the inhibitory effect of microRNAs (miRNA) on the 3′-untranslated region (3′-UTR) of HNF-4A mRNA. The potential recognition elements of a set of miRNAs were identified utilizing bioinformatics analysis. The family members of miR-34 and miR-449, including miR-34a, miR-34c-5p and miR-449a, share the same target elements located at two distinct locations within the 3′-UTR of HNF-4A. The over-expression of miR-34a, miR-34c-5p or miR-449a in HepG2 cells led to a significant decrease in the activity of luciferase reporter carrying 3′-UTR of HNF-4A. The repressive effect on reporter activity was partially or fully eliminated when one or two of the binding site(s) for miR-34a/miR-34c-5p/miR-449a were deleted within the 3′-UTR. The protein level of HNF-4α was dramatically reduced by over-expression of miR-34a, miR-34c-5p and miR-449a, which correlates with a decrease in the binding activity of HNF-4α and transactivation of HNF-4α target genes. These results suggest that the recognition sites of miR-34a, miR-34c-5p and miR-449a within 3′-UTR of HNF-4A are functional. The mechanism of down-regulation of the binding activity and transactivation of HNF-4α by the miRNAs involves the decrease in HNF-4α protein level via miRNAs selectively targeting HNF-4A 3’-UTR, leading to the translational repression of HNF-4α expression.
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影响因子：
64.5
作者：
Hatziapostolou M;Polytarchou C;Aggelidou E;Drakaki A;Poultsides GA;Jaeger SA;Ogata H;Karin M;Struhl K;Hadzopoulou-Cladaras M;Iliopoulos D
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通讯作者：
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16
作者：
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通讯作者：
Talianidis, I
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16
作者：
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通讯作者：
Talianidis, I