Abstract
Retroviruses have been foundational in cancer research since early studies identified proto-oncogenes as targets for insertional mutagenesis. Integration of murine gamma-retroviruses into the host genome favours promoters and enhancers and entails interaction of viral integrase with host BET/bromodomain factors. We report that this integration pattern is conserved in feline leukaemia virus (FeLV), a gamma-retrovirus that infects many human cell types. Analysis of FeLV insertion sites in the MCF-7 mammary carcinoma cell line revealed strong bias towards active chromatin marks with no evidence of significant post-integration growth selection. The most prominent FeLV integration targets had little overlap with the most abundantly expressed transcripts, but were strongly enriched for annotated cancer genes. A meta-analysis based on several gamma-retrovirus integration profiling (GRIP) studies in human cells (CD34+, K562, HepG2) revealed a similar cancer gene bias but also remarkable cell-type specificity, with prominent exceptions including a universal integration hotspot at the long non-coding RNA MALAT1. Comparison of GRIP targets with databases of super-enhancers from the same cell lines showed that these have only limited overlap and that GRIP provides unique insights into the upstream drivers of cell growth. These observations elucidate the oncogenic potency of the gamma-retroviruses and support the wider application of GRIP to identify the genes and growth regulatory circuits that drive distinct cancer types.
Highlights
The ability of retroviruses to direct stable integration is inherently mutagenic and can perturb host cell genes at the proviral insertion site or even at a significant distance [1,2]
This study shows that gamma-retrovirus integration in human cells is skewed towards cancer driver genes in a highly cell-type specific manner
While gamma-retroviruses have been widely used as cancer gene discovery tools due to their insertional mutagenic potential in their natural hosts, this approach required the onerous task of collecting multiple end-stage tumours from animal models and comparative genomic analyses to confirm the relevance of findings to human cancer [5,6,7,11,30]
Summary
The ability of retroviruses to direct stable integration is inherently mutagenic and can perturb host cell genes at the proviral insertion site or even at a significant distance [1,2]. The non-randomness of murine leukemia virus (MLV) integration was first appreciated from early studies that highlighted biases towards DNaseI hypersensitive sites and transcriptional start sites [12] The basis of this specificity was recently elucidated with the demonstration that the MLV integrase interacts with BET/bromodomain proteins (Brd and 4) that in turn bind to acetylated histone H3K27ac, marking some of the most active regions of chromatin [13,14,15]. The importance of this interaction is underlined by the significant reduction in titre and/or loss of TSS targeting of MLV grown in the presence of BET inhibitors JQ1 and I-BET in vitro [13,14,15]. This creates a further connection with cancer research as BET inhibitors are currently being investigated in clinical trials for the treatment of multiple cancers [16]
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