Abstract
BackgroundTransposable 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Transposable elements (TE) are commonly regarded as “junk DNA” with no apparent regulatory roles in the human genome
TE-derived promoter activity was correlated with epigenetic derepression To further characterise these TE-derived promoters, we investigated whether they displayed differential methylation in breast cancer tumours and whether they resided in open chromatin in breast cancer cell lines, by analysing published whole-genome methylation capture sequencing and DNase-seq datasets [64, 65]
TEs serve as a supply of binding sites for RNA polymerases and transcription factor enzymes, and can influence host gene expression by providing promoter or enhancer activities
Summary
Transposable elements (TE) are commonly regarded as “junk DNA” with no apparent regulatory roles in the human genome. McClintock’s theory was initially dismissed, and the prevailing view was that TEs were “junk” or “selfish” DNA sequences with no apparent regulatory roles [5,6,7]. In more recent years, McClintock’s theory of TEs as gene expression regulators has been revised and refined by emerging evidence showing that they do play a role in modulating and reshaping host transcriptional regulatory networks [8,9,10,11]. The regulatory activity of TEs is derived from the cis-regulatory elements within their sequences, which include internal promoters and binding sites that can be recognised by host transcription factors (TF) and RNA The regulatory roles of TEs are not rare events exclusive to plants, but are common to almost all eukaryotic evolutionary lineages, including humans [12,13,14].
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