Abstract
LINE-1 retrotransposons are abundant repetitive elements of viral origin, which in normal cells are kept quiescent through epigenetic mechanisms. Activation of LINE-1 occurs frequently in cancer and can enable LINE-1 mobilization but also has retrotransposition-independent consequences. We previously reported that in cancer, aberrantly active LINE-1 promoters can drive transcription of flanking unique sequences giving rise to LINE-1 chimeric transcripts (LCTs). Here, we show that one such LCT, LCT13, is a large transcript (>300 kb) running antisense to the metastasis-suppressor gene TFPI-2. We have modelled antisense RNA expression at TFPI-2 in transgenic mouse embryonic stem (ES) cells and demonstrate that antisense RNA induces silencing and deposition of repressive histone modifications implying a causal link. Consistent with this, LCT13 expression in breast and colon cancer cell lines is associated with silencing and repressive chromatin at TFPI-2. Furthermore, we detected LCT13 transcripts in 56% of colorectal tumours exhibiting reduced TFPI-2 expression. Our findings implicate activation of LINE-1 elements in subsequent epigenetic remodelling of surrounding genes, thus hinting a novel retrotransposition-independent role for LINE-1 elements in malignancy.
Highlights
Tumourigenesis is accompanied by multiple genetic and epigenetic changes that promote cell proliferation and escape from growth arrest [1]
Given that antisense transcripts have been shown to silence genes in diseases including cancer [34,35] and that expressed sequence tags (ESTs) annotations indicate the potential for large antisense transcripts in this region, we investigated whether LCT13 transcripts originating at the L1 element and an antisense promoter (L1-ASP) could act as antisense transcripts to tissue factor pathway inhibitor (TFPI)-2
Downregulation of TFPI-2 was found in a third patient without any detectable LCT13 and TFPI-2as expression, a finding likely to reflect multiple mechanisms leading to loss of expression of this gene in cancer [41]
Summary
Tumourigenesis is accompanied by multiple genetic and epigenetic changes that promote cell proliferation and escape from growth arrest [1]. Epigenetic alterations include disruption of DNA methylation patterns, changes in histone modifications and nucleosome positioning, contributing to modified gene expression [2]. Changes to DNA methylation in cancer are well characterized, with both genome-wide hypomethylation at repetitive sequences such as retrotransposons and hypermethylation of CpG island (CGI) genes present within the same malignant cell type [3,4]. The molecular mechanisms underlying these epigenetic aberrancies remain elusive; but it is possible that a relationship exists between genome-wide changes in DNA modifications and alterations in gene expression [4,5,6,7]. Commensurate with this, hypomethylation-induced activation of L1s has been proposed to promote cancer progression and genomic instability [10,11,12] due to retrotransposition events [13,14,15], and recent evidence confirms the presence of new somatic L1 insertions in the tumours of patients with lung and colon cancer [16,17]
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