An integrative genomic approach identifies p73 and p63 as activators of miR-200 microRNA family transcription.
An integrative genomic approach identifies p73 and p63 as activators of miR-200 microRNA family transcription.
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DOI：
10.1093/nar/gkr731
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发表时间：
2012-01
影响因子：
14.9
通讯作者：
Tewari M
中科院分区：
文献类型：
--
作者：
Knouf EC;Garg K;Arroyo JD;Correa Y;Sarkar D;Parkin RK;Wurz K;O'Briant KC;Godwin AK;Urban ND;Ruzzo WL;Gentleman R;Drescher CW;Swisher EM;Tewari M
尽管microRNAs （miRNAs）是基因表达的重要调控因子，但miRNAs本身的转录调控尚不清楚。我们采用综合计算管道来剖析卵巢癌中导致miRNA表达改变的转录因子（TFs）。利用实验数据和计算预测来定义整个人类基因组中的miRNA启动子，我们确定了在卵巢癌中miRNA基因过表达中结合位点明显过高的tf。该管道提名p53/p63/p73家族的tf作为miRNA过表达的候选驱动因素。对The Cancer Genome Atlas中独立的253例卵巢癌的数据分析表明，p73和p63的表达与启动子含有p53/p63/p73家族结合位点的mirna的表达显著相关。在实验验证中，我们发现p53/p63/p73家族结合位点可以调节miR-200家族mirna的启动子活性，而miR-200家族是癌症干细胞和上皮间质转化的调节因子。此外，在染色质免疫沉淀研究中，p73和p63与miR-200b/a/429启动子直接相关。本研究描述了一种可以应用于发现其他生物环境中类似基因组数据的转录调控机制的综合方法。
Although microRNAs (miRNAs) are important regulators of gene expression, the transcriptional regulation of miRNAs themselves is not well understood. We employed an integrative computational pipeline to dissect the transcription factors (TFs) responsible for altered miRNA expression in ovarian carcinoma. Using experimental data and computational predictions to define miRNA promoters across the human genome, we identified TFs with binding sites significantly overrepresented among miRNA genes overexpressed in ovarian carcinoma. This pipeline nominated TFs of the p53/p63/p73 family as candidate drivers of miRNA overexpression. Analysis of data from an independent set of 253 ovarian carcinomas in The Cancer Genome Atlas showed that p73 and p63 expression is significantly correlated with expression of miRNAs whose promoters contain p53/p63/p73 family binding sites. In experimental validation of specific miRNAs predicted by the analysis to be regulated by p73 and p63, we found that p53/p63/p73 family binding sites modulate promoter activity of miRNAs of the miR-200 family, which are known regulators of cancer stem cells and epithelial–mesenchymal transitions. Furthermore, in chromatin immunoprecipitation studies both p73 and p63 directly associated with the miR-200b/a/429 promoter. This study delineates an integrative approach that can be applied to discover transcriptional regulatory mechanisms in other biological settings where analogous genomic data are available.
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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：
3.7
作者：
Galic, Vijaya;Willner, Julia;Swisher, Elizabeth M.
通讯作者：
Swisher, Elizabeth M.
影响因子：
11.2
作者：
Hendrix, ND;Wu, R;Cho, KR
通讯作者：
Cho, KR
影响因子：
11.2
作者：
Ibrahim, Nageatte;He, Lei;Ellisen, Leif W.
通讯作者：
Ellisen, Leif W.
影响因子：
64.8
作者：
He, Lin;He, Xingyue;Hannon, Gregory J.
通讯作者：
Hannon, Gregory J.