Human transposons are an abundant supply of transcription factor binding sites and promoter activities in breast cancer cell lines

Abstract

Background Transposable elements (TE) are commonly regarded as “junk DNA” with no apparent regulatory roles in the human genome. However, a growing body of evidence demonstrates that some TEs exhibit regulatory activities in a range of biological pathways and diseases, with notable examples in bile metabolism and innate immunity. TEs are typically suppressed by epigenetic modifications in healthy somatic tissues, which prevents both undesirable effects of insertional mutagenesis, and also unwanted gene activation. Interestingly, TEs are widely reported to be dysregulated in epithelial cancers, and while much attention has been paid to their effects on genome instability, relatively little has been reported on their effects on gene regulation. Here, we investigated the contribution of TEs to the transcriptional regulation in breast cancer cell lines. Results We found that a subset of TE subfamilies were enriched in oncogenic transcription factor binding sites and also harboured histone marks associated with active transcription, raising the possibility of these subfamilies playing a broad role in breast cancer transcriptional regulation. To directly assess promoter activity in triple negative breast cancer cell lines, we identified four breast cancer-associated genes with putative TE-derived promoters. TE deletion confirmed a contribution to promoter activity in all cases, and for two examples the promoter activity was almost completely contained within the TE. Conclusions Our findings demonstrate that TEs provide abundant oncogenic transcription factor binding sites in breast cancer and that individual TEs contain substantial promoter activity. Our findings provide further evidence for transcriptional regulation of human genes through TE exaptation by demonstrating the regulatory potential of TEs in multiple breast cancer cell lines. Electronic supplementary material The online version of this article (10.1186/s13100-019-0158-3) contains supplementary material, which is available to authorized users.

L1PA2 transposons contribute abundant regulatory sequences in MCF7 breast cancer cell line

“…Our analysis revealed that the L1PA2 transposons were significantly enriched in E2F1 and MYC binding sites in MCF7 cells. Furthermore, luciferase assays in triple negative breast cancer cells confirmed the activity of an L1PA2-derived promoter, where the transposon was found to account for a significant proportion of promoter activity to the SYT1 gene (Jiang and Upton 2019). In support of our findings, a recent paper by Jang et al showed that the L1PA2-derived promoter activity was not limited to SYT1, and was also seen for other oncogenes, such as MET, XCL1…”

“…We previously reported the regulatory activity of several transposon subfamilies in the context of breast cancer (Jiang and Upton 2019). Our analysis revealed that the L1PA2 transposons were significantly enriched in E2F1 and MYC binding sites in MCF7 cells.…”

“…More specifically, a hypo-methylated L1PA2 transposon is found to act as an alternate promoter to the MET oncogene in breast cancer, chronic myeloid leukemia and colorectal cancer, and the L1PA2-MET expression is associated with enhanced malignancy and poor prognosis (Roman-Gomez et al 2005;Weber et al 2010;Hur et al 2014;Miglio et al 2018). In the context of breast cancer, we previously identified enriched E2F1 and MYC binding sites in the L1PA2 subfamily, and demonstrated that L1PA2 contributed the significant promoter activity for the SYT1 oncogene in triple negative breast cancer cell lines (Jiang and Upton 2019). Intrigued by these results, we hypothesised that this regulatory activity was conserved across the L1PA2 subfamily, and performed an integrated in silico analysis of L1PA2derived TF binding and promoter activity in breast cancer cells.…”

Specialized DNA structures act as genomic beacons for integration by evolutionarily diverse retroviruses

“…SINEs (e.g. Alu repeats) and other transposed sequences are known to serve as direct silencers of gene expression due to their repressed chromatin marks (histone H3 methylated at Lys 9) ( 69 , 70 ). Moreover, non-B DNA structures such as G4, cruciform, triplex and Z-DNA have been shown to silence expression of adjacent genes ( 65 , 71 , 80 , 72 – 79 ).…”

Antiretroviral APOBEC3 Cytidine Deaminases Alter HIV-1 Provirus Integration Site Profiles

“…SINEs (e.g. Alu repeats) and other transposed sequences are known to serve as direct silencers of gene expression due to their repressed chromatin marks (histone H3 methylated at Lys9) [72][73][74] . Moreover, some non-B DNA structures including G4, cruciform, triplex and Z-DNA have been shown to potently silence expression of adjacent genes [75][76][77][78][79][80][81][82][83][84][85] .…”