Department of Molecular Cancer Research, University Medical Centre, Utrecht, The Netherlands.
Mol Syst Biol. 2013;9:638. 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.
叉头框 O (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 FOXO3 激活的全基因组效应。聚合酶 II 变化分析表明，FOXO3 通过转录起始调节基因表达。FOXO3 和 RNA 聚合酶 II ChIP-seq 图谱的相关分析表明，FOXO3 作为转录激活剂发挥作用。此外，该分析揭示了 FOXO3 基因调控的很大一部分是通过增强子区域进行的。FOXO3 结合到预先存在的增强子上，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，FOXO3 介导的增强子激活与相邻基因的调节以及 FOXO3 结合的增强子和靶基因之间染色质环的预先存在相关。总之，我们的数据阐明了 FOXO 如何调节基因转录，并深入了解了 FOXO 如何根据染色质结构诱导不同的基因表达程序的机制。
