LINE-1 retrotransposons are a plentiful and cunning repetitive element of viral origin, which are typically kept silent via our hardworking epigenetic mechanism: DNA methylation. However, just like every good molecular pirate, cancer likes to use what it hijacks. Dr. Cristina Tufarelli’s group (University of Nottingham, UK) have previously shown that aberrant activation of LINE-1 promoters can drive the transcription of it’s unsuspecting neighbors, giving rise to “LINE-1 chimeric transcripts (LCTs)”. In their most recent research, Tufarelli’s group wanted to examine the functional consequences of these LCTs by modeling antisense RNA expression in transgenic mouse embryonic stem (ES) cells.
They demonstrated that:
- Activation of a retrotransposon (LINE-1) and silencing of a metastasis suppressor gene (TFPI-2) appear to be mechanistically linked events in cancer.
- Antisense RNA (LCT-13) expression, driven by aberrant LINE-1 activation, is associated with transcriptional silencing and the placement of repressive histone modifications at TFPI-2.
- These results hint at a general mechanism: Aberrantly active LINE-1 promoters may drive RNA transcription of chimeric transcripts and trigger epigenetic silencing of complimentary protective genes.
It is widely believed that LINE-1 activation is a consequence of the genome-wide hypomethylation observed in cancer since DNA methylation has been proposed as a defence mechanism against those retrotransposable pirates. However, the mechanisms leading to genome-wide hypomethylation are unclear and whether the same mechanisms are responsible for activation of LINE-1 elements still remains unknown.
For those of you who don’t research cancer, fear not, the authors still suggest a take home message for the rest of the community. Given that that the an abundance of non-coding RNAs initiate at retrotransposable elements, it appears that LINE-1 driven transcription may play important regulatory roles in normal development and differentiation. The mechanisms observed in this research could be more widespread than previously thought and be as relevant to normal development and differentiation as to disease progression. But that’s yet to be shown.
Read on in Nucleic Acids Research, May 2013