MicroRNA-125a is over-expressed in insulin target tissues in a spontaneous rat model of Type 2 Diabetes.
MicroRNA-125a is over-expressed in insulin target tissues in a spontaneous rat model of Type 2 Diabetes.
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DOI：
10.1186/1755-8794-2-54
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发表时间：
2009-08-18
影响因子：
2.7
通讯作者：
Lindgren CM
中科院分区：
文献类型：
--
作者：
Herrera BM;Lockstone HE;Taylor JM;Wills QF;Kaisaki PJ;Barrett A;Camps C;Fernandez C;Ragoussis J;Gauguier D;McCarthy MI;Lindgren CM
MicroRNAs(MiRNAs)是一种非编码的RNA分子，参与转录后调控多种基因的表达，包括那些参与葡萄糖动态平衡的基因。2型糖尿病(T2D)的特征是高血糖和胰岛素分泌和作用于靶组织的缺陷。我们试图从自发性糖尿病和正常血糖品系的近交系大鼠的两个胰岛素靶组织中建立全球miRNA表达的差异。我们使用miRNA微阵列平台测量了两个胰岛素靶组织：自发性糖尿病(Goto-Kakizaki[GK])和正常血糖(Brown-挪威[BN])品系近交系大鼠的肝脏和脂肪组织中miRNA的全球表达，这两种品系广泛用于T2D的遗传学研究。MiRNA数据与来自同一大鼠的基因表达数据相结合，以研究差异表达的miRNAs如何影响预测的目标基因转录本的表达。检测GK和BN大鼠肝脏和脂肪组织中170个miRNAs的表达。根据GK和BN之间差异表达的p值，观察到miR-125a在肝脏中的表达变化最显著(FC=5.61，P=0.001，P=0.10)；定量RT-PCR法证实了这种过度表达(FC=13.15，P=0.0005)。在脂肪组织内的GK和BN分析中，miR-125a也显示出高表达(FC=1.97，P=0.078，P=0.99)，与先前报道的miR-29a一样(FC=1.5 1，P=0.0 5，P=0.99)。评估预测的miR-125a目标基因的生物学作用的电子工具表明，参与MAPK信号通路的基因过度表达。基因表达分析发现GK大鼠和BN大鼠之间有1308个差异表达基因(P<0.05)：233个在肝脏，1075个在脂肪组织。在这些基因中，与糖和脂代谢相关的途径明显过多。浓缩分析表明，与BN相比，GK中差异表达的基因包含了比在脂肪组织中偶然预期的更多的miR-125a靶基因(上调基因的FDR=0.006；下调基因的FDR=0.036)，但在肝脏中没有(上调基因的FDR=0.074；下调基因的FDR=0.248)。与正常血糖的BN大鼠相比，MIR-125a在高血糖GK大鼠的肝脏中过表达，我们的阵列数据也表明miR-125a在脂肪组织中过表达。我们演示了In-Silicon工具的使用，为进一步研究miR-125a在T2D中的潜在作用提供了基础。特别是，预测的miR-125a靶基因在差异表达基因中的丰富已经确定了可能的靶基因，并表明整合全球miRNA和mRNA表达数据可能会进一步深入了解miRNA介导的基因表达调控。
MicroRNAs (miRNAs) are non-coding RNA molecules involved in post-transcriptional control of gene expression of a wide number of genes, including those involved in glucose homeostasis. Type 2 diabetes (T2D) is characterized by hyperglycaemia and defects in insulin secretion and action at target tissues. We sought to establish differences in global miRNA expression in two insulin-target tissues from inbred rats of spontaneously diabetic and normoglycaemic strains. We used a miRNA microarray platform to measure global miRNA expression in two insulin-target tissues: liver and adipose tissue from inbred rats of spontaneously diabetic (Goto-Kakizaki [GK]) and normoglycaemic (Brown-Norway [BN]) strains which are extensively used in genetic studies of T2D. MiRNA data were integrated with gene expression data from the same rats to investigate how differentially expressed miRNAs affect the expression of predicted target gene transcripts. The expression of 170 miRNAs was measured in liver and adipose tissue of GK and BN rats. Based on a p-value for differential expression between GK and BN, the most significant change in expression was observed for miR-125a in liver (FC = 5.61, P = 0.001, Padjusted = 0.10); this overexpression was validated using quantitative RT-PCR (FC = 13.15, P = 0.0005). MiR-125a also showed over-expression in the GK vs. BN analysis within adipose tissue (FC = 1.97, P = 0.078, Padjusted = 0.99), as did the previously reported miR-29a (FC = 1.51, P = 0.05, Padjusted = 0.99). In-silico tools assessing the biological role of predicted miR-125a target genes suggest an over-representation of genes involved in the MAPK signaling pathway. Gene expression analysis identified 1308 genes with significantly different expression between GK and BN rats (Padjusted < 0.05): 233 in liver and 1075 in adipose tissue. Pathways related to glucose and lipid metabolism were significantly over-represented among these genes. Enrichment analysis suggested that differentially expressed genes in GK compared to BN included more predicted miR-125a target genes than would be expected by chance in adipose tissue (FDR = 0.006 for up-regulated genes; FDR = 0.036 for down-regulated genes) but not in liver (FDR = 0.074 for up-regulated genes; FDR = 0.248 for down-regulated genes). MiR-125a is over-expressed in liver in hyperglycaemic GK rats relative to normoglycaemic BN rats, and our array data also suggest miR-125a is over-expressed in adipose tissue. We demonstrate the use of in-silico tools to provide the basis for further investigation of the potential role of miR-125a in T2D. In particular, the enrichment of predicted miR-125a target genes among differentially expressed genes has identified likely target genes and indicates that integrating global miRNA and mRNA expression data may give further insights into miRNA-mediated regulation of gene expression.
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影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
影响因子：
56.9
作者：
Lagos-Quintana, M;Rauhut, R;Tuschl, T
通讯作者：
Tuschl, T
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
64.5
作者：
Lewis, BP;Shih, IH;Burge, CB
通讯作者：
Burge, CB
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y