L1 retrotransposons are the only autonomous mobile elements in the human genome (1). Due to the potential deleterious effect of their mobilisation, L1s are repressed in most circumstances (2). Yet, L1s are active in embryonic development and in epithelial cancers (1, 3). To date, the molecular mechanisms that activate L1 retrotransposition are unknown.
There are certain molecular pathways shared between epithelial cancers and embryonic development. In both contexts, cells are required to change in phenotype to be able to migrate (4). The mechanism that enables this is Epithelial to Mesenchymal Transition (EMT). EMT is triggered by signalling pathways, such as TGF-B, Notch and Wnt, that activate a network of transcription factors that act as both repressors of epithelial genes and activators of mesenchymal genes (5).
As EMT and L1 activation take place in the same context, we hypothesise that EMT activates L1 retrotransposition.
Analysis of RNA-seq expression data from 200 tumour samples (The Cancer Genome Atlas Project) shows that genes involved in EMT correlate positively with L1 activity associated genes, gene set enrichment score FDR q-val= 0.004. Furthermore, qRT-PCR measuring L1 mRNA levels before and after EMT induction shows a significant increase in L1 mRNA abundance after in vitro EMT induction.
Our data strongly suggest that induction of EMT activates L1 transcription.
This is the first evidence for the identification of the molecular pathway leading to L1 activation.