Dataset integration identifies transcriptional regulation of microRNA genes by PPARγ in differentiating mouse 3T3-L1 adipocytes.
Dataset integration identifies transcriptional regulation of microRNA genes by PPARγ in differentiating mouse 3T3-L1 adipocytes.
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DOI：
10.1093/nar/gks025
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发表时间：
2012-05
影响因子：
14.9
通讯作者：
Sinkkonen L
中科院分区：
文献类型：
--
作者：
John E;Wienecke-Baldacchino A;Liivrand M;Heinäniemi M;Carlberg C;Sinkkonen L
过氧化物酶体增殖物激活受体γ（Peroxisome proliferator-activated receptor γ，PPARγ）是哺乳动物脂肪形成的关键转录因子。全基因组方法已经在小鼠脂肪细胞中鉴定出数千个PPARγ结合位点，并且在脂肪形成过程中，PPARγ上调数百个蛋白质编码基因。然而，没有microRNA（miRNA）基因被鉴定为主要的PPARγ靶点。通过整合3 T3-L1脂肪细胞中全基因组范围的PPARγ结合位点的四个独立数据集，我们鉴定了距离miRNA转录起始位点50 kb内具有PPARγ结合的98个miRNA簇。在脂肪形成过程中，19种成熟的miRNA上调≥2倍，其中6种miRNA位点的PPARγ结合位点被至少3个数据集证实。5个miRNA基因miR-103-1（宿主基因Pank 3）、miR-148 b（Copz 1）、miR-182/96/183、miR-205和miR-378（Ppargc 1b）的上调跟随Pparg的上调。通过PPARγ敲低证实了其中4个miRNA位点的PPARγ依赖性，并且miR-103-1（Pank 3）、miR-205和miR-378（Ppargc 1b）位点也对PPARγ配体罗格列酮有反应。最后，通过计算机模拟验证染色质免疫沉淀分析预测了所有三个基因座的PPARγ结合位点，并分析了H3 K27乙酰化，以确认这些增强子的活性。总之，我们鉴定了22个假定的PPARγ靶miRNA基因，显示了其中4个基因的PPARγ依赖性，并证明了3个在小鼠脂肪形成中作为直接的PPARγ靶基因。
Peroxisome proliferator-activated receptor γ (PPARγ) is a key transcription factor in mammalian adipogenesis. Genome-wide approaches have identified thousands of PPARγ binding sites in mouse adipocytes and PPARγ upregulates hundreds of protein-coding genes during adipogenesis. However, no microRNA (miRNA) genes have been identified as primary PPARγ-targets. By integration of four separate datasets of genome-wide PPARγ binding sites in 3T3-L1 adipocytes we identified 98 miRNA clusters with PPARγ binding within 50 kb from miRNA transcription start sites. Nineteen mature miRNAs were upregulated ≥2-fold during adipogenesis and for six of these miRNA loci the PPARγ binding sites were confirmed by at least three datasets. The upregulation of five miRNA genes miR-103-1 (host gene Pank3), miR-148b (Copz1), miR-182/96/183, miR-205 and miR-378 (Ppargc1b) followed that of Pparg. The PPARγ-dependence of four of these miRNA loci was demonstrated by PPARγ knock-down and the loci of miR-103-1 (Pank3), miR-205 and miR-378 (Ppargc1b) were also responsive to the PPARγ ligand rosiglitazone. Finally, chromatin immunoprecipitation analysis validated in silico predicted PPARγ binding sites at all three loci and H3K27 acetylation was analyzed to confirm the activity of these enhancers. In conclusion, we identified 22 putative PPARγ target miRNA genes, showed the PPARγ dependence of four of these genes and demonstrated three as direct PPARγ target genes in mouse adipogenesis.
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影响因子：
14.9
作者：
Han L;Zhou R;Niu J;McNutt MA;Wang P;Tong T
通讯作者：
Tong T
影响因子：
4.8
作者：
Hamm, JK;Park, BH;Farmer, SR
通讯作者：
Farmer, SR
影响因子：
56.9
作者：
Farh, KKH;Grimson, A;Bartel, DP
通讯作者：
Bartel, DP
影响因子：
64.5
作者：
Marson A;Levine SS;Cole MF;Frampton GM;Brambrink T;Johnstone S;Guenther MG;Johnston WK;Wernig M;Newman J;Calabrese JM;Dennis LM;Volkert TL;Gupta S;Love J;Hannett N;Sharp PA;Bartel DP;Jaenisch R;Young RA
通讯作者：
Young RA
影响因子：
3.7
作者：
Ortega FJ;Moreno-Navarrete JM;Pardo G;Sabater M;Hummel M;Ferrer A;Rodriguez-Hermosa JI;Ruiz B;Ricart W;Peral B;Fernández-Real JM
通讯作者：
Fernández-Real JM