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首页> 外文期刊>Cancer Management and Research >Super-Enhancer-Associated Hub Genes In Chronic Myeloid Leukemia Identified Using Weighted Gene Co-Expression Network Analysis
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Super-Enhancer-Associated Hub Genes In Chronic Myeloid Leukemia Identified Using Weighted Gene Co-Expression Network Analysis

机译：使用加权基因共同表达网络分析鉴定慢性骨髓性白血病中的超强增强子相关枢纽基因

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Purpose: Super-enhancer (SE)-associated oncogenes extensively potentiate the uncontrolled proliferation capacity of cancer cells. In this study, we aimed to identify the SE-associated hub genes associated with the clinical characteristics of chronic myeloid leukemia (CML). Methods: Eigengenes from CML clinical modules were determined using weighted gene co-expression network analysis (WGCNA). Overlapping genes between eigengenes and SE-associated genes were used to construct protein–protein interaction (PPI) networks and annotate for pathway enrichment analysis. Expression patterns of the top-ranked SE-associated hub genes were further determined in CML patients and healthy controls via real-time PCR. After treatment of K562 cells with the BRD4 inhibitor, JQ1, for 24 hrs, mRNA and protein levels of SE-associated hub genes were evaluated using real-time PCR and Western blotting, respectively. H3K27ac, H3K4me1 and BRD4 ChIP-seq signal peaks were used to predict and identify SEs visualized by the Integrative Genomics Viewer. Results: The yellow module was significantly related to the status and pathological phase of CML. SE-associated hub candidate genes were mainly enriched in the cell cycle pathway. Based on the PPI networks of hub genes and the top rank of degree, five SE-associated genes were identified: specifically, BUB1, CENPO, KIF2C, ORC1 , and RRM2 . Elevated expression of these five genes was not only related to CML status and phase but also positively regulated by SE and suppressed by the BRD4 inhibitor, JQ1, in K562 cells. Strong signal peaks of H3K27ac, H3K4me1 and BRD4 ChIP-seq of the five genes were additionally observed close to the predicted SE regions. Conclusion: This is the first study to characterize SE-associated genes linked to clinical characteristics of CML via weighted gene co-expression network analysis. Our results support a novel mechanism involving aberrant expression of hub SE-associated genes in CML patients and K562 cells, and these genes will be potential new therapeutic targets for human leukemia.
机译：目的：超级增强剂（SE） - 致癌的癌症，广泛提高癌细胞的不受控制的增殖能力。在这项研究中，我们旨在鉴定与慢性髓性白血病（CML）的临床特征相关的SE相关的轮毂基因。方法：使用加权基因共表达网络分析（WGCNA）测定CML临床模块的eIgengenes。使用EIGENGENES和SE相关基因之间的重叠基因用于构建蛋白质 - 蛋白质相互作用（PPI）网络并注释途径富集分析。通过实时PCR进一步在CML患者和健康对照中进一步测定顶级Se相关轮毂基因的表达模式。在用BRD4抑制剂的k562细胞处理K562细胞后，使用实时PCR和Western印迹评估Se相关枢纽基因的24小时，MRNA和蛋白质水平。 H3K27AC，H3K4ME1和BRD4芯片SEQ信号峰值用于预测和识别由综合基因组学观察可视化的SES。结果：黄色模块与CML的状态和病理相显着相关。 Se相关的轮毂候选基因主要富集在细胞周期途径中。基于集线基因的PPI网络和最大程度的程度，确定了五种相关基因：特别是Bub1，CenPo，KIF 2 C，ORC1和RRM2。这五种基因的升高表达不仅与CML状态和相有关，而且通过SE阳性调节并被BRD4抑制剂，JQ1在K562细胞中抑制。另外观察到五个基因的H3K27AC，H3K4ME1和BRD4芯片-Seq的强信号峰。结论：这是第一项研究表征与CML的临床特征相关的SE相关基因通过加权基因共表达网络分析。我们的研究结果支持一种新的机制，涉及CML患者和K562细胞中的HUB SE相关基因的异常表达，这些基因将是人白血病的潜在新的治疗靶标。

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