ChIP-seq defined genome-wide map of TGFβ/SMAD4 targets: implications with clinical outcome of ovarian cancer.
ChIP-seq defined genome-wide map of TGFβ/SMAD4 targets: implications with clinical outcome of ovarian cancer.
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DOI：
10.1371/journal.pone.0022606
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Jin VX
中科院分区：
文献类型：
--
作者：
Kennedy BA;Deatherage DE;Gu F;Tang B;Chan MW;Nephew KP;Huang TH;Jin VX
上皮性卵巢癌中转化生长因子-β（TGFβ）信号通路的失调已有报道，但该疾病中TGFβ信号通路中断的确切机制仍不清楚。我们进行染色质免疫沉淀，然后测序（ChIP-seq），以研究上皮性卵巢癌中TGFβ诱导的SMAD 4结合的全基因组筛选。在TGFβ刺激A2780上皮性卵巢癌细胞系后，我们鉴定了2，362个SMAD 4结合位点和318个差异表达的SMAD 4靶基因。SMAD 4结合基因座的全面检查揭示了四种不同的结合模式：1）基础; 2）偏移; 3）仅刺激; 4）仅未刺激。TGFβ刺激的SMAD 4结合位点主要分为仅刺激（74%）或偏移（25%），表明TGFβ刺激改变上皮性卵巢癌细胞中SMAD 4结合模式。此外，基于基因调控网络分析，我们确定了TGFβ诱导的SMAD 4依赖性调控网络在卵巢癌中与正常细胞相比有显著不同。重要的是，基于对可获得的患者数据库的计算机挖掘，在A2780上皮性卵巢癌细胞系中鉴定的TGFβ/SMAD 4靶基因预测患者存活。总之，我们的数据强调了下一代测序技术在识别上皮性卵巢癌中全基因组SMAD 4靶基因并将异常TGFβ/SMAD信号传导与卵巢肿瘤发生联系起来方面的实用性。此外，所鉴定的SMAD 4结合位点与基因表达谱分析和患者队列的计算机数据挖掘相结合，可以提供一种强有力的方法来确定卵巢癌和其他癌症的生物学和未来翻译研究的潜在基因特征。
Deregulation of the transforming growth factor-β (TGFβ) signaling pathway in epithelial ovarian cancer has been reported, but the precise mechanism underlying disrupted TGFβ signaling in the disease remains unclear. We performed chromatin immunoprecipitation followed by sequencing (ChIP-seq) to investigate genome-wide screening of TGFβ-induced SMAD4 binding in epithelial ovarian cancer. Following TGFβ stimulation of the A2780 epithelial ovarian cancer cell line, we identified 2,362 SMAD4 binding loci and 318 differentially expressed SMAD4 target genes. Comprehensive examination of SMAD4-bound loci, revealed four distinct binding patterns: 1) Basal; 2) Shift; 3) Stimulated Only; 4) Unstimulated Only. TGFβ stimulated SMAD4-bound loci were primarily classified as either Stimulated only (74%) or Shift (25%), indicating that TGFβ-stimulation alters SMAD4 binding patterns in epithelial ovarian cancer cells. Furthermore, based on gene regulatory network analysis, we determined that the TGFβ-induced, SMAD4-dependent regulatory network was strikingly different in ovarian cancer compared to normal cells. Importantly, the TGFβ/SMAD4 target genes identified in the A2780 epithelial ovarian cancer cell line were predictive of patient survival, based on in silico mining of publically available patient data bases. In conclusion, our data highlight the utility of next generation sequencing technology to identify genome-wide SMAD4 target genes in epithelial ovarian cancer and link aberrant TGFβ/SMAD signaling to ovarian tumorigenesis. Furthermore, the identified SMAD4 binding loci, combined with gene expression profiling and in silico data mining of patient cohorts, may provide a powerful approach to determine potential gene signatures with biological and future translational research in ovarian and other cancers.
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影响因子：
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通讯作者：
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DOI：
10.1073/pnas.0605333103
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