MicroRNA and transcription factor co-regulatory network analysis reveals miR-19 inhibits CYLD in T-cell acute lymphoblastic leukemia.
MicroRNA and transcription factor co-regulatory network analysis reveals miR-19 inhibits CYLD in T-cell acute lymphoblastic leukemia.
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MicroRNA和转录因子共调控网络分析揭示miR-19抑制T细胞急性淋巴细胞白血病中的CYLD
DOI：
10.1093/nar/gks175
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发表时间：
2012-07
影响因子：
14.9
通讯作者：
Guo AY
中科院分区：
文献类型：
--
作者：
Ye H;Liu X;Lv M;Wu Y;Kuang S;Gong J;Yuan P;Zhong Z;Li Q;Jia H;Sun J;Chen Z;Guo AY
T细胞急性淋巴细胞白血病（T - ALL）是一种侵袭性的血液系统恶性肿瘤。对其基因表达调控和分子机制的了解仍然难以捉摸。从经过实验验证的与T - ALL相关的微小RNA（miRNA）和基因出发，我们通过结合靶点预测获得了120个在T - ALL相关基因、miRNA和转录因子（TF）之间的前馈环路（FFL）。之后，构建了一个T - ALL的miRNA和TF共同调控网络，并通过统计方法检验了其显著性。在miR - 17 - 92簇中的4种miRNA以及4个重要基因（CYLD、HOXA9、BCL2L11和RUNX1）被发现是该网络中的关键节点。特别地，我们发现miR - 19在T - ALL患者和细胞系中高表达。miR - 19的异位表达抑制CYLD表达，而miR - 19抑制剂处理诱导CYLD蛋白表达，并降低下游信号通路中的NF - κB表达。因此，miR - 19、CYLD和NF - κB形成一个调控性的前馈环路，这为T - ALL中NF - κB的持续激活提供了新的线索。综上所述，我们提供了T - ALL中的首个miRNA - TF共同调控网络，并提出了一个模型来展示miR - 19和CYLD在T细胞白血病发生中的作用。这项研究可能为T - ALL提供潜在的治疗靶点，并为在复杂疾病研究中将生物信息学与实验相结合提供启示。
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. The understanding of its gene expression regulation and molecular mechanisms still remains elusive. Started from experimentally verified T-ALL-related miRNAs and genes, we obtained 120 feed-forward loops (FFLs) among T-ALL-related genes, miRNAs and TFs through combining target prediction. Afterwards, a T-ALL miRNA and TF co-regulatory network was constructed, and its significance was tested by statistical methods. Four miRNAs in the miR-17–92 cluster and four important genes (CYLD, HOXA9, BCL2L11 and RUNX1) were found as hubs in the network. Particularly, we found that miR-19 was highly expressed in T-ALL patients and cell lines. Ectopic expression of miR-19 represses CYLD expression, while miR-19 inhibitor treatment induces CYLD protein expression and decreases NF-κB expression in the downstream signaling pathway. Thus, miR-19, CYLD and NF-κB form a regulatory FFL, which provides new clues for sustained activation of NF-κB in T-ALL. Taken together, we provided the first miRNA-TF co-regulatory network in T-ALL and proposed a model to demonstrate the roles of miR-19 and CYLD in the T-cell leukemogenesis. This study may provide potential therapeutic targets for T-ALL and shed light on combining bioinformatics with experiments in the research of complex diseases.
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影响因子：
56.9
作者：
Kim, Jongpil;Inoue, Keiichi;Abeliovich, Asa
通讯作者：
Abeliovich, Asa
Mirbase：MicroRNA基因组学的工具。
影响因子：
14.9
作者：
Griffiths-Jones, Sam;Saini, Harpreet Kaur;van Dongen, Stijn;Enright, Anton J.
通讯作者：
Enright, Anton J.
影响因子：
20.3
作者：
Gutierrez, Alejandro;Sanda, Takaomi;Look, A. Thomas
通讯作者：
Look, A. Thomas
影响因子：
14.9
作者：
Betel D;Wilson M;Gabow A;Marks DS;Sander C
通讯作者：
Sander C
影响因子：
3.6
作者：
Lappas, M;Permezel, M;Rice, GE
通讯作者：
Rice, GE