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Cruickshanks, H.A and Vafadar-Isfahani, N. and Dunican, D.S. and Lee, A. and Sproul, D. and Lund, Jonathan N. and Meehan, R.R. and 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). pp. 6857-6869. ISSN 0305-1048

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.

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