Cruickshanks, H.A, Vafadar-Isfahani, N., Dunican, D.S., Lee, A., Sproul, D., Lund, Jonathan N., 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
Full text not available from this repository.
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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