Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma
Mapping of transcription factor motifs in active chromatin identifies IRF5 as key regulator in classical Hodgkin lymphoma
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DOI：
10.1073/pnas.1406985111
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发表时间：
2014-10-21
影响因子：
11.1
通讯作者：
Mathas, Stephan
中科院分区：
文献类型：
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作者：
Kreher, Stephan;Bouhlel, M. Amine;Mathas, Stephan
转录因子（TF）活性失调是常见的造血系统恶性肿瘤。因此，了解肿瘤发生需要确定单个TF的功能和分级作用。为了确定TF中央淋巴瘤的发生，我们确定了淋巴瘤类型特异性的DNA酶I超敏位点的全球映射，并分析了丰富的TF结合基序在这些地区的染色质。将这种无偏的方法应用于经典霍奇金淋巴瘤（HL），一种常见的B细胞来源的淋巴瘤，具有复杂的转录因子失调模式，我们发现了干扰素调节因子（IRF）的网站之间的顶部丰富的图案。高水平表达的促炎性TF IRF5是特定于HL细胞和他们的生存至关重要。此外，IRF 5通过诱导TF AP-1并与NF-κ B协同激活HL的基本特征，在人非霍奇金B细胞系和原代鼠B细胞中启动调节级联反应。我们的策略有效地鉴定了淋巴瘤类型特异性关键调节因子，并揭示了IRF5的肿瘤促进作用。
Deregulated transcription factor (TF) activities are commonly observed in hematopoietic malignancies. Understanding tumorigenesis therefore requires determining the function and hierarchical role of individual TFs. To identify TFs central to lymphomagenesis, we identified lymphoma type-specific accessible chromatin by global mapping of DNaseI hypersensitive sites and analyzed enriched TF-binding motifs in these regions. Applying this unbiased approach to classical Hodgkin lymphoma (HL), a common B-cell-derived lymphoma with a complex pattern of deregulated TFs, we discovered interferon regulatory factor (IRF) sites among the top enriched motifs. High-level expression of the proinflammatory TF IRF5 was specific to HL cells and crucial for their survival. Furthermore, IRF5 initiated a regulatory cascade in human non-Hodgkin B-cell lines and primary murine B cells by inducing the TF AP-1 and cooperating with NF-kappa B to activate essential characteristic features of HL. Our strategy efficiently identified a lymphoma type-specific key regulator and uncovered a tumor promoting role of IRF5.