Integrative ChIP-seq/microarray analysis identifies a CTNNB1 target signature enriched in intestinal stem cells and colon cancer.
Integrative ChIP-seq/microarray analysis identifies a CTNNB1 target signature enriched in intestinal stem cells and colon cancer.
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DOI：
10.1371/journal.pone.0092317
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Dai X
中科院分区：
文献类型：
--
作者：
Watanabe K;Biesinger J;Salmans ML;Roberts BS;Arthur WT;Cleary M;Andersen B;Xie X;Dai X
典型Wnt/CTNNB1 （β -连环蛋白）通路的解除管制是结肠癌发病的最早事件之一。APC或CTNNB1突变在结肠癌中非常常见，并导致CTNNB1异常稳定，CTNNB1通过TCF/LEF转录因子与染色质结合，激活Wnt靶基因的转录。在这里，我们报告了一项通过染色质免疫沉淀结合高通量测序（ChIP-seq）和基因表达谱通过微阵列分析对结肠癌细胞中rnai介导的CTNNB1敲低进行全基因组染色质占用的综合分析。我们在整个基因组中观察到3629个CTNNB1结合峰，CTNNB1结合与敲低诱导的基因表达变化之间存在显著相关性。我们的综合分析发现了一个由162个基因组成的直接Wnt靶信号。对该信号的基因本体分析显示Wnt通路基因显著富集，提示该通路存在多重反馈调控。我们提供的证据表明，该基因标记部分与Lgr5+肠道干细胞标记重叠，并且在正常肠道干细胞和临床结直肠癌样本中显著富集。有趣的是，虽然CTNNB1靶基因集的表达与生存无关，但信号中负反馈调节因子的表达升高预示着更好的预后。我们的数据提供了结肠癌细胞中Wnt/CTNNB1信号的染色质占用和基因调控的全基因组视图。
Deregulation of canonical Wnt/CTNNB1 (beta-catenin) pathway is one of the earliest events in the pathogenesis of colon cancer. Mutations in APC or CTNNB1 are highly frequent in colon cancer and cause aberrant stabilization of CTNNB1, which activates the transcription of Wnt target genes by binding to chromatin via the TCF/LEF transcription factors. Here we report an integrative analysis of genome-wide chromatin occupancy of CTNNB1 by chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) and gene expression profiling by microarray analysis upon RNAi-mediated knockdown of CTNNB1 in colon cancer cells. We observed 3629 CTNNB1 binding peaks across the genome and a significant correlation between CTNNB1 binding and knockdown-induced gene expression change. Our integrative analysis led to the discovery of a direct Wnt target signature composed of 162 genes. Gene ontology analysis of this signature revealed a significant enrichment of Wnt pathway genes, suggesting multiple feedback regulations of the pathway. We provide evidence that this gene signature partially overlaps with the Lgr5+ intestinal stem cell signature, and is significantly enriched in normal intestinal stem cells as well as in clinical colorectal cancer samples. Interestingly, while the expression of the CTNNB1 target gene set does not correlate with survival, elevated expression of negative feedback regulators within the signature predicts better prognosis. Our data provide a genome-wide view of chromatin occupancy and gene regulation of Wnt/CTNNB1 signaling in colon cancer cells.
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