Computational identification of the normal and perturbed genetic networks involved in myeloid differentiation and acute promyelocytic leukemia.
Computational identification of the normal and perturbed genetic networks involved in myeloid differentiation and acute promyelocytic leukemia.
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DOI：
10.1186/gb-2008-9-2-r38
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发表时间：
2008
期刊：
影响因子：
12.3
通讯作者：
Stormo GD
中科院分区：
文献类型：
--
作者：
Chang LW;Payton JE;Yuan W;Ley TJ;Nagarajan R;Stormo GD
解剖遗传网络和电路描述了两种形式的白血病。整合转录因子结合和基因表达谱，揭示了这一重要人类疾病背后的网络。急性髓系白血病（AML）是一组以恶性髓系细胞异常发育为特征的疾病。最近的研究表明，异常转录调控在AML病理生理中起着重要作用。尽管一些参与髓细胞发育和白血病的转录因子（TFs）已经被广泛而独立地研究过，但这些转录因子如何与其他转录因子协调，以及它们的失调如何扰乱髓细胞分化的遗传回路尚不清楚。我们提出了一种结合基因表达谱分析和TF结合位点鉴定的综合方法来构建哺乳动物遗传网络。我们利用我们的方法构建了正常髓细胞分化与急性早幼粒细胞白血病（APL） （AML的一种亚型）之间的遗传回路。在正常和疾病网络中，我们发现多个转录调控级联分别集中在TFs Rora和Rxra上。此外，在APL中失调的tf参与了一个共同的调控途径，并可能通过Fos扰乱正常的网络。最后，提出了一种嵌合TF PML-RARα通过六种中介TF激活APL失调的发病机制模型。本报告展示了我们的方法在构建哺乳动物遗传网络方面的实用性，并获得了关于在人类复杂疾病中运作的调控回路的新见解。
A dissection of the genetic networks and circuitries is described for two form of leukaemia. Integrating transcription factor binding and gene expression profiling, networks are revealed that underly this important human disease. Acute myeloid leukemia (AML) comprises a group of diseases characterized by the abnormal development of malignant myeloid cells. Recent studies have demonstrated an important role for aberrant transcriptional regulation in AML pathophysiology. Although several transcription factors (TFs) involved in myeloid development and leukemia have been studied extensively and independently, how these TFs coordinate with others and how their dysregulation perturbs the genetic circuitry underlying myeloid differentiation is not yet known. We propose an integrated approach for mammalian genetic network construction by combining the analysis of gene expression profiling data and the identification of TF binding sites. We utilized our approach to construct the genetic circuitries operating in normal myeloid differentiation versus acute promyelocytic leukemia (APL), a subtype of AML. In the normal and disease networks, we found that multiple transcriptional regulatory cascades converge on the TFs Rora and Rxra, respectively. Furthermore, the TFs dysregulated in APL participate in a common regulatory pathway and may perturb the normal network through Fos. Finally, a model of APL pathogenesis is proposed in which the chimeric TF PML-RARα activates the dysregulation in APL through six mediator TFs. This report demonstrates the utility of our approach to construct mammalian genetic networks, and to obtain new insights regarding regulatory circuitries operating in complex diseases in humans.
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影响因子：
5.3
作者：
Degols, G;Russell, P
通讯作者：
Russell, P
DOI：
10.1073/pnas.0404731101
发表时间：
2004-09-07
影响因子：
11.1
作者：
Helbling, D;Mueller, BU;Pabst, T
通讯作者：
Pabst, T
影响因子：
10.5
作者：
GIGUERE, V;TINI, M;OTULAKOWSKI, G
通讯作者：
OTULAKOWSKI, G
影响因子：
11.4
作者：
Dahl, R;Ramirez-Bergeron, DL;Simon, MC
通讯作者：
Simon, MC
影响因子：
15.3
作者：
Giannola, DM;Shlomchik, WD;Emerson, SG
通讯作者：
Emerson, SG