title: Expression of a large LINE-1-driven antisense RNA is linked to epigenetic silencing of the metastasis suppressor gene TFPI-2 in cancer.
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.
authors.affiliation: Wolfson Centre for Stem Cells, Tissue Engineering and Modelling (STEM), School of Clinical Sciences, University of Nottingham, Centre for Biomedical Sciences, Nottingham NG7 2RD, UK.
authors.forename: Hazel A
authors.initials: HA
authors.lastname: Cruickshanks
authors.forename: Natasha
authors.initials: N
authors.lastname: Vafadar-Isfahani
authors.forename: Donncha S
authors.initials: DS
authors.lastname: Dunican
authors.forename: Andy
authors.initials: A
authors.lastname: Lee
authors.forename: Duncan
authors.initials: D
authors.lastname: Sproul
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Lund
authors.forename: Richard R
authors.initials: RR
authors.lastname: Meehan
authors.forename: Cristina
authors.initials: C
authors.lastname: Tufarelli
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D061986:MCF-7 Cells; D051379:Mice; D016372:RNA, Antisense / Q000737:chemistry / Q000378:metabolism*
chemical_list: D006023:Glycoproteins; D016372:RNA, Antisense; C021240:tissue-factor-pathway inhibitor 2