Expression of a large LINE-1-driven antisense RNA is linked to epigenetic silencing of the metastasis suppressor gene TFPI-2 in cancer

Cruickshanks, H.A; Vafadar-Isfahani, N.; Dunican, D.S.; Lee, A.; Sproul, D.; Lund, Jonathan N.; Meehan, R.R.; Tufarelli, C.

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.

Citation

Cruickshanks, H., Vafadar-Isfahani, N., Dunican, D., Lee, A., Sproul, D., Lund, J. N., …Tufarelli, C. Expression of a large LINE-1-driven antisense RNA is linked to epigenetic silencing of the metastasis suppressor gene TFPI-2 in cancer. Nucleic Acids Research, 41(14), https://doi.org/10.1093/nar/gkt438

• Journal Article Type: Article
• Deposit Date: Nov 1, 2013
• Journal: Nucleic Acids Research
• Print ISSN: 0305-1048
• Electronic ISSN: 0305-1048
• Publisher: Oxford University Press
• Peer Reviewed: Peer Reviewed
• Volume: 41
• Issue: 14
• DOI: https://doi.org/10.1093/nar/gkt438
• Public URL: https://nottingham-repository.worktribe.com/output/1026019
• Publisher URL: http://nar.oxfordjournals.org/content/41/14/6857