Expression of a large LINE-1-driven antisense RNA is linked to epigenetic silencing of the metastasis suppressor gene TFPI-2 in cancer
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 pre...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Published: |
Oxford Journals
|
| Online Access: | https://eprints.nottingham.ac.uk/2212/ |
| _version_ | 1848790732018548736 |
|---|---|
| author | Cruickshanks, H.A Vafadar-Isfahani, N. Dunican, D.S. Lee, A. Sproul, D. Lund, Jonathan N. Meehan, R.R. Tufarelli, C. |
| author_facet | Cruickshanks, H.A Vafadar-Isfahani, N. Dunican, D.S. Lee, A. Sproul, D. Lund, Jonathan N. Meehan, R.R. Tufarelli, C. |
| author_sort | Cruickshanks, H.A |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T18:17:17Z |
| format | Article |
| id | nottingham-2212 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T18:17:17Z |
| publisher | Oxford Journals |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-22122020-05-04T20:34:29Z https://eprints.nottingham.ac.uk/2212/ 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. 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. Oxford Journals Article PeerReviewed 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 http://nar.oxfordjournals.org/content/41/14/6857 doi:10.1093/nar/gkt438 doi:10.1093/nar/gkt438 |
| spellingShingle | Cruickshanks, H.A Vafadar-Isfahani, N. Dunican, D.S. Lee, A. Sproul, D. Lund, Jonathan N. Meehan, R.R. 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 |
| title | Expression of a large LINE-1-driven antisense RNA
is linked to epigenetic silencing of the metastasis
suppressor gene TFPI-2 in cancer |
| title_full | Expression of a large LINE-1-driven antisense RNA
is linked to epigenetic silencing of the metastasis
suppressor gene TFPI-2 in cancer |
| title_fullStr | Expression of a large LINE-1-driven antisense RNA
is linked to epigenetic silencing of the metastasis
suppressor gene TFPI-2 in cancer |
| title_full_unstemmed | Expression of a large LINE-1-driven antisense RNA
is linked to epigenetic silencing of the metastasis
suppressor gene TFPI-2 in cancer |
| title_short | Expression of a large LINE-1-driven antisense RNA
is linked to epigenetic silencing of the metastasis
suppressor gene TFPI-2 in cancer |
| title_sort | expression of a large line-1-driven antisense rna
is linked to epigenetic silencing of the metastasis
suppressor gene tfpi-2 in cancer |
| url | https://eprints.nottingham.ac.uk/2212/ https://eprints.nottingham.ac.uk/2212/ https://eprints.nottingham.ac.uk/2212/ |