Genome-wide analysis of FOXO3 mediated transcription regulation through RNA polymerase II profiling
Genome-wide analysis of FOXO3 mediated transcription regulation through RNA polymerase II profiling
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DOI：
10.1038/msb.2012.74
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发表时间：
2013-01-01
影响因子：
9.9
通讯作者：
Burgering, Boudewijn M. T.
中科院分区：
文献类型：
--
作者：
Eijkelenboom, Astrid;Mokry, Michal;Burgering, Boudewijn M. T.
叉头盒0（FOXO）转录因子是影响肿瘤发生、干细胞维持和寿命的多种细胞过程中的关键参与者。为了深入了解FOXO调节靶基因表达的机制，我们研究了FOXO 3激活的全基因组效应。分析RNA聚合酶II的变化表明，FOXO 3通过转录起始调节基因表达。FOXO 3和RNA聚合酶II ChIP-seq图谱的相关性分析表明FOXO 3作为转录激活因子。此外，该分析揭示了FOXO 3基因调控的重要部分通过增强子区域进行。FOXO 3结合到预先存在的增强子，并进一步激活这些增强子，如组蛋白乙酰化和RNA聚合酶II募集的变化所示。此外，FOXO 3介导的增强子激活与相邻基因的调节以及FOXO 3结合增强子和靶基因之间染色质环的预先存在相关。结合，我们的数据阐明了FOXO如何调节基因转录，并提供了FOXO可以诱导不同的基因表达程序取决于染色质结构的机制的见解。Molecular Systems Biology 9：638; 2013年1月22日在线发表; doi：10.1038/msb.2012.74
Forkhead box O (FOXO) transcription factors are key players in diverse cellular processes affecting tumorigenesis, stem cell maintenance and lifespan. To gain insight into the mechanisms of FOXO-regulated target gene expression, we studied genome-wide effects of FOXO3 activation. Profiling RNA polymerase II changes shows that FOXO3 regulates gene expression through transcription initiation. Correlative analysis of FOXO3 and RNA polymerase II ChIP-seq profiles demonstrates FOXO3 to act as a transcriptional activator. Furthermore, this analysis reveals a significant part of FOXO3 gene regulation proceeds through enhancer regions. FOXO3 binds to pre-existing enhancers and further activates these enhancers as shown by changes in histone acetylation and RNA polymerase II recruitment. In addition, FOXO3-mediated enhancer activation correlates with regulation of adjacent genes and pre-existence of chromatin loops between FOXO3 bound enhancers and target genes. Combined, our data elucidate how FOXOs regulate gene transcription and provide insight into mechanisms by which FOXOs can induce different gene expression programs depending on chromatin architecture. Molecular Systems Biology 9: 638; published online 22 January 2013; doi:10.1038/msb.2012.74