Three-dimensional analysis reveals altered chromatin interaction by enhancer inhibitors harbors TCF7L2-regulated cancer gene signature
Three-dimensional analysis reveals altered chromatin interaction by enhancer inhibitors harbors TCF7L2-regulated cancer gene signature
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DOI：
10.1002/jcb.27449
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发表时间：
2019-03-01
影响因子：
4
通讯作者：
Frietze, Seth E.
中科院分区：
文献类型：
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作者：
Gerrard, Diana L.;Wang, Yao;Frietze, Seth E.
远端调控元件通过染色质成环影响基因启动子的活性。染色体构象捕获（3C）方法允许识别基因组不同区域的染色质接触。然而，由于这些方法的分辨率的限制，功能性染色质相互作用的检测仍然是一个挑战。在目前的研究中，我们采用一种综合的方法来定义和表征人胰腺癌细胞的功能性染色质接触。我们应用系留染色质捕获来定义全基因组范围内的染色质结构域类别。我们确定了三种类型的结构域（拓扑相关，边界和间隙），并研究了这些结构域与染色质状态和基因表达的功能关系。我们发现了与表观遗传状态相关的六个不同的子域。有趣的是，特定的表观遗传活性结构域对组蛋白乙酰转移酶（HAT）抑制剂治疗敏感，并降低H3K27乙酰化水平。为了检查药物治疗后改变的亚结构域是否与转录因子调控功能相关，我们将TCF7L2染色质结合和基因调控与HAT抑制进行了比较。我们确定了一个编码RNA基因的子集，这些基因可以将胰腺癌患者分为不同的生存组。总的来说，这项研究描述了一个过程，以评估染色体结构的功能特征，并揭示了表观遗传抑制剂对染色体结构的影响，并确定基因，可能提供深入了解疾病的结果。
Distal regulatory elements influence the activity of gene promoters through chromatin looping. Chromosome conformation capture (3C) methods permit identification of chromatin contacts across different regions of the genome. However, due to limitations in the resolution of these methods, the detection of functional chromatin interactions remains a challenge. In the current study, we employ an integrated approach to define and characterize the functional chromatin contacts of human pancreatic cancer cells. We applied tethered chromatin capture to define classes of chromatin domains on a genome-wide scale. We identified three types of structural domains (topologically associated, boundary, and gap) and investigated the functional relationships of these domains with respect to chromatin state and gene expression. We uncovered six distinct sub-domains associated with epigenetic states. Interestingly, specific epigenetically active domains are sensitive to treatment with histone acetyltransferase (HAT) inhibitors and decrease in H3K27 acetylation levels. To examine whether the subdomains that change upon drug treatment are functionally linked to transcription factor regulation, we compared TCF7L2 chromatin binding and gene regulation to HAT inhibition. We identified a subset of coding RNA genes that together can stratify pancreatic cancer patients into distinct survival groups. Overall, this study describes a process to evaluate the functional features of chromosome architecture and reveals the impact of epigenetic inhibitors on chromosome architecture and identifies genes that may provide insight into disease outcome.