Novel mechanisms of retrovirus-induced transcription activation in mouse tumors. Deregulations are shown using normalized transcription coverage as BedGraphs . Coverage on the plus and minus strand is colored red and blue, respectively. The upper panel in each subfigure (A-E) shows the transcription profile of a tumor containing a provirus. The lower panel shows the mean coverage of tumors without known integrations at the loci shown. Horizontal green lines mark integration clusters, and the number of proviruses from RTCGD and the BALB/c and NMRI datasets as well as the sizes of clusters are indicated. Vertical green arrows mark positions of proviruses identified in RNA-seq and orientations are indicated by black arrows. The deregulations in subfigures A, C and E are shown in detail in Figure 4. (A) Bidirectional activation. Integration induces upregulation of Klf7, activation of a large 165 kb unannotated region (dashed line), and local transcription activation at the provirus (red arrow). (B) Tandem-type activation. Integration at Ccr9 activates Lztfl1 and Slc6a20a, which are positioned adjacently on the DNA minus strand, as well as transcription of opposite polarity in the region in between these two genes (red arrow). (C) Sense/antisense activation. Integration downstream of Syn2 activates transcription from both DNA strands resulting in expression of non-coding AK038749 (red arrow) and Syn2. (D) Activation of genes that are not targets of integration. Col4a5 functions as a hotspot for retroviral integrations that activate expression of the distal gene Irs4, without affecting expression of Col4a5 itself. Integration clusters marked with arrow heads indicate that proviruses share the same orientation. (E) Combination-type activation. Enhancer activation mutagenesis, promoter insertion and alternative splicing are used simultaneously by a single provirus to alter the expression pattern of Celf2. The red arrow marks increased transcriptional activity in the intron containing the provirus (described in the main text).