Transposable Elements in Oncogenic Transformation
Open AccessTransposable Elements (TEs) are DNA sequences that can move about the genome and are typically silenced in normal tissues. TEs are normally silenced through DNA methylation and histone modifications. In cancer, global perturbations in TE regulation lead to their transcription. This transcription can have various effects on gene expression, genomic stability, and mutagenesis. TE activation can also provide alternate promoters for oncogene transcription and disrupt tumor suppressors, but also activates immune signaling which can be leveraged through epigenetic and immunotherapies. Cancer progression models, which study the early stages of tumorigenesis, can shed light on the role of TEs and identify specific TEs activated in the earliest cancer stages.We assessed expression and DNA methylation of TEs in three models of oncogenic transformation. In the Weinberg Transformation Model, fibroblast cells were serially transduced with hTERT, SV40, and HRASR24C to immortalize and then transform them, modeling the different steps of the tumorigenesis process. We also assessed TE transcription in immortalized FT cells compared to normal fallopian tube endothelial (NFTE) cells. Finally, we assessed DNA methylation of TEs in an ovarian cancer-specific model, in which immortalized fallopian tube cells from donors with three different mutational backgrounds were transformed via transduction of HRASR24C or cMYC. RNA-sequencing and whole-genome bisulfite sequencing were performed at each stage of transformation. In both the Weinberg and immortalized vs NFTE models, TE expression significantly increased during immortalization/transformation, consistent with data from human tumors. The upregulated TEs were dominated by endogenous retroviruses (LTRs). Most differentially methylated regions (DMRs) in both the Weinberg and OC-specific transformation model were hypomethylated after transformation. A majority of the DMRs overlapped TEs from the RepeatMasker database, indicating that TEs are preferentially demethylated. Many hypomethylated TEs displayed a concordant increase in expression. In the Weinberg Transformation Model, demethylation began during immortalization and continued into transformation, while upregulation of TE transcription occurred after transformation. Numerous LTR elements upregulated in the model were also identified in TCGA datasets of breast, colon, and prostate cancer. Overall, these findings indicate that transposable elements, specifically endogenous retroviruses, are demethylated and transcribed during transformation.
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