A deep investigation into the adipogenesis mechanism: profile of microRNAs regulating adipogenesis by modulating the canonical Wnt/beta-catenin signaling pathway.
A deep investigation into the adipogenesis mechanism: profile of microRNAs regulating adipogenesis by modulating the canonical Wnt/beta-catenin signaling pathway.
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DOI：
10.1186/1471-2164-11-320
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发表时间：
2010-05-23
期刊：
影响因子：
4.4
通讯作者：
Mo D
中科院分区：
文献类型：
--
作者：
Qin L;Chen Y;Niu Y;Chen W;Wang Q;Xiao S;Li A;Xie Y;Li J;Zhao X;He Z;Mo D
MicroRNAs （miRNAs）是一类微小的非编码rna (~22- 24nt)，通过控制mRNA的稳定性或翻译在转录后水平调节多种生物过程。作为一种分子开关，典型的Wnt/β-catenin信号通路在脂肪形成过程中应被抑制；然而，这一途径的激活导致脂库形成的抑制。我们研究的目的是确定可能通过调节WNT信号通路参与脂肪形成的mirna。在此，我们建立了激活和抑制WNT信号的两种细胞模型，并利用微阵列技术研究了microrna的表达谱。高通量芯片数据显示，18种mirna可能通过抑制WNT信号传导促进脂肪形成：miR-210、miR-148a、miR-194、miR-322等。同时，我们还发现了29个可能通过激活WNT信号而对脂肪形成产生负面影响的mirna: miR-344、miR-27和miR-181等。这些mirna的靶点也通过生物信息学进行了分析。为了验证这些已鉴定的mirna的预测靶标和潜在功能，将miR-210的模拟物转染到3T3-L1细胞中，观察到具有不同脂滴的增大细胞；同时，转染miR-210抑制剂可在转录水平显著降低分化特异性因子，提示miR-210在促进脂肪形成中的特殊作用。Tcf7l2是miR-210的预测靶标，是一种触发WNT信号下游应答基因的转录因子，在转录水平上被阻断。此外，在HEK-293FT细胞中，与miR-210共转染后，携带Tcf7l2 mRNA 3' UTR的荧光素酶报告基因的活性降低。最后，转染miR-210后，锂（LiCl）处理的3T3-L1细胞中β-catenin的蛋白表达水平升高。这些发现表明miR-210可以通过靶向Tcf7l2抑制WNT信号传导来促进脂肪形成。结果表明，mirna存在于两种细胞模型中，为WNT通路特异性mirna提供了见解，这些mirna可以进一步表征其在脂肪形成中的潜在作用。据我们所知，本研究首次尝试揭示了通过调节WNT信号通路参与脂肪形成的mirna图谱，有助于深入研究脂肪形成的机制。
MicroRNAs (miRNAs) are a large class of tiny non-coding RNAs (~22-24 nt) that regulate diverse biological processes at the posttranscriptional level by controlling mRNA stability or translation. As a molecular switch, the canonical Wnt/β-catenin signaling pathway should be suppressed during the adipogenesis; However, activation of this pathway leads to the inhibition of lipid depots formation. The aim of our studies was to identify miRNAs that might be involved in adipogenesis by modulating WNT signaling pathway. Here we established two types of cell model, activation and repression of WNT signaling, and investigated the expression profile of microRNAs using microarray assay. The high throughput microarray data revealed 18 miRNAs that might promote adipogenesis by repressing WNT signaling: miR-210, miR-148a, miR-194, miR-322 etc. Meanwhile, we also identified 29 miRNAs that might have negative effect on adipogenesis by activating WNT signaling: miR-344, miR-27 and miR-181 etc. The targets of these miRNAs were also analysed by bioinformatics. To validate the predicted targets and the potential functions of these identified miRNAs, the mimics of miR-210 were transfected into 3T3-L1 cells and enlarged cells with distinct lipid droplets were observed; Meanwhile, transfection with the inhibitor of miR-210 could markedly decrease differentiation-specific factors at the transcription level, which suggested the specific role of miR-210 in promoting adipogenesis. Tcf7l2, the predicted target of miR-210, is a transcription factor triggering the downstream responsive genes of WNT signaling, was blocked at transcription level. Furthermore, the activity of luciferase reporter bearing Tcf7l2 mRNA 3' UTR was decreased after co-transfection with miR-210 in HEK-293FT cells. Last but not least, the protein expression level of β-catenin was increased in the lithium (LiCl) treated 3T3-L1 cells after transfection with miR-210. These findings suggested that miR-210 could promote adipogenesis by repressing WNT signaling through targeting Tcf7l2. The results suggest the presence of miRNAs in two cell models, providing insights into WNT pathway-specific miRNAs that can be further characterized for their potential roles in adipogenesis. To our knowledge, present study represents the first attempt to unveil the profile of miRNAs involed in adipogenesis by modulating WNT signaling pathway, which contributed to deeper investigation of the mechanism of adipogenesis.
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影响因子：
14.9
作者：
Chen C;Ridzon DA;Broomer AJ;Zhou Z;Lee DH;Nguyen JT;Barbisin M;Xu NL;Mahuvakar VR;Andersen MR;Lao KQ;Livak KJ;Guegler KJ
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Christodoulides, Constantinos;Lagathu, Claire;Sethi, Jaswinder K.;Vidal-Puig, Antonio
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