RESUMO
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.
Assuntos
Retrovirus Endógenos/genética , Regulação Neoplásica da Expressão Gênica/genética , Doença de Hodgkin/genética , Fatores Reguladores de Interferon/genética , Sequências Repetidas Terminais/genética , Evolução Molecular , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ativação TranscricionalRESUMO
Malignancy results from a complex combination of genetic and epigenetic changes, the full effects of which are still largely unknown. Here we summarize current knowledge of the origin, retrotranspositional activity, epigenetic state, and transcription of human endogenous retroviruses (HERVs), and then discuss the potential effects of their deregulation in cancer. Evidence suggests that cancer-associated epigenetic changes most likely underlie potential HERV-mediated effects on genome and transcriptome instability and may play a role in malignancy. Despite our currently limited understanding of the importance of HERVs or other transposable elements in cancer development, we believe that the emerging era of high-throughput sequencing of cancer genomes, epigenomes, and transcriptomes will provide unprecedented opportunities to investigate these roles in the future.
