Transposable Elements Regulate Oncogene Expression in Human Cancers

Activation of epigenetically silenced transposable elements (TE) is a recently identified mechanism of oncogene activation known as onco-exaptation. Although it has been shown in specific cancer types, onco-exaptation has yet to be comprehensively analyzed as a widespread mechanism for oncogene activation. In an analysis of RNA-sequencing data from 7,769 tumor samples and 625 tumor-matched normal samples, Jang, Shah, and colleagues identified oncogene–TE chimeric transcripts in nearly 50% of all tumors. The most prevalent onco-exaptation events accounted for more than 50% of target gene expression, and up to 90% of oncogene expression in some tumors. Among highly expressed TE-regulated oncogenes was the fusion transcript AluJb–LIN28B, coding for an additional 22 amino acids on the N terminus of LIN28B. Paired-end CAGE sequencing in two lung cancer cell lines confirmed a cryptic transcription start site within the AluJb promoter 20 kb upstream of the LIN28B promoter. The AluJb promoter was completely methylated in somatic cells and either wholly or partially demethylated in cancer cells; demethylation was accompanied by an open chromatin state and active epigenetic marks. Targeted methylation or demethylation of the AluJb promoter decreased or increased expression of the AluJb–LIN28B fusion, respectively. Motif analysis identified binding motifs for C/EBPD, SP1, SP4, and YY1 transcription factors within the AluJb promoter, and luciferase reporter assays demonstrated a loss of activity following deletion or mutation of these motifs. Deletion of the AluJb promoter, but not the LIN28B promoter, eliminated expression of the fusion protein, resulting in increased levels of LIN28B target miRNAs, slower growth and migration in vitro, and defective tumor growth in vivo; reexpression of LIN28B partially reversed these effects. Taken together, these findings show that dynamic DNA methylation within the cell can activate regulatory elements within oncogene-associated TEs to drive tumor progression. Onco-exaptation is thus a widespread mechanism of oncogene activation and represents a potential target for therapeutic intervention.

Jang HS, Shah NM, Du AY, Dailey ZZ, Pehrsson EC, Godoy PM, et al. Transposable elements drive widespread expression of oncogenes in human cancers. Nat Gen 2019;51:611–7.

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