Oncogene-mediated alterations in chromatin conformation
Oncogene-mediated alterations in chromatin conformation
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DOI：
10.1073/pnas.1112570109
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发表时间：
2012-06-05
影响因子：
11.1
通讯作者：
Rubin, Mark A.
中科院分区：
文献类型：
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作者：
Rickman, David S.;Soong, T. David;Rubin, Mark A.
新出现的证据表明，染色质采用非随机的三维拓扑结构，基因的组织结构枢纽和域影响其转录状态。染色质构象在癌症等疾病中如何变化还知之甚少。此外，如何致癌转录因子，结合到整个基因组的数千个位点，影响基因调控，通过全局改变染色质的拓扑结构需要进一步的调查。为了解决这些问题，我们进行了公正的高分辨率映射内和染色体间的相互作用后，ERG，一种致癌转录因子经常过度表达的前列腺癌作为基因融合的结果过度表达。通过整合来自全基因组染色体构象捕获（Hi-C）、ERG结合和基因表达的数据，我们证明致癌转录因子过表达与染色质组织的全局性、可重复性和功能一致性变化相关。这里呈现的结果具有更广泛的意义，因为其他癌症类型的基因组改变经常引起异常转录因子表达，例如，例如，在一个实施例中，EWS-FLI1、c-Myc、n-Myc和PML-RAR α。
Emerging evidence suggests that chromatin adopts a nonrandom 3D topology and that the organization of genes into structural hubs and domains affects their transcriptional status. How chromatin conformation changes in diseases such as cancer is poorly understood. Moreover, how oncogenic transcription factors, which bind to thousands of sites across the genome, influence gene regulation by globally altering the topology of chromatin requires further investigation. To address these questions, we performed unbiased high-resolution mapping of intra- and interchromosome interactions upon overexpression of ERG, an oncogenic transcription factor frequently overexpressed in prostate cancer as a result of a gene fusion. By integrating data from genome-wide chromosome conformation capture (Hi-C), ERG binding, and gene expression, we demonstrate that oncogenic transcription factor overexpression is associated with global, reproducible, and functionally coherent changes in chromatin organization. The results presented here have broader implications, as genomic alterations in other cancer types frequently give rise to aberrant transcription factor expression, e. g., EWS-FLI1, c-Myc, n-Myc, and PML-RAR alpha.