Onco-exaptation of an endogenous retroviral LTR drives IRF5 expression in Hodgkin lymphoma
Onco-exaptation of an endogenous retroviral LTR drives IRF5 expression in Hodgkin lymphoma
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DOI：
10.1038/onc.2015.308
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发表时间：
2016-05-12
期刊：
影响因子：
8
通讯作者：
Mager, D. L.
中科院分区：
文献类型：
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作者：
Babaian, A.;Romanish, M. T.;Mager, D. L.
转录因子干扰素调节因子5 （IRF5）在霍奇金淋巴瘤（HL）中上调，是该疾病异常转录组特征的关键调节因子。本研究表明，HL中IRF5的上调是由IRF5上游正常休眠的内源性逆转录病毒LOR1a长末端重复序列（LTR）的转录激活驱动的。具体来说，通过筛选rna测序文库，我们在多种HL细胞系中检测到LTR-IRF5嵌合转录物，但在正常b细胞对照中未检测到。在HL中，LTR处于开放和低甲基化的表观遗传状态，我们进一步证明LTR是转录起始位点。在HL细胞系中，LTR启动子的使用与IRF5 mRNA和蛋白的总体水平密切相关，表明LTR转录觉醒是HL中IRF5上调的主要因素。综上所述，HL中致癌IRF5过表达是特异性LTR转录激活的结果。我们认为这种LTR抑制是一种独特的致癌基因激活机制（“onco- exapation”），这种机制值得在分子和癌症研究中进一步研究。
The transcription factor interferon regulatory factor 5 (IRF5) is upregulated in Hodgkin lymphoma (HL) and is a key regulator of the aberrant transcriptome characteristic of this disease. Here we show that IRF5 upregulation in HL is driven by transcriptional activation of a normally dormant endogenous retroviral LOR1a long terminal repeat (LTR) upstream of IRF5. Specifically, through screening of RNA-sequencing libraries, we detected LTR-IRF5 chimeric transcripts in multiple HL cell lines but not in normal B-cell controls. In HL, the LTR was in an open and hypomethylated epigenetic state, and we further show the LTR is the site of transcriptional initiation. Among HL cell lines, usage of the LTR promoter strongly correlates with overall levels of IRF5 mRNA and protein, indicating that LTR transcriptional awakening is a major contributor to IRF5 upregulation in HL. Taken together, oncogenic IRF5 overexpression in HL is the result of a specific LTR transcriptional activation. We propose that such LTR derepression is a distinct mechanism of oncogene activation ('onco-exaptation'), and that such a mechanism warrants further investigation in molecular and cancer research.