Transdifferentiation of Mouse Embryonic Fibroblasts into Dopaminergic Neurons Reactivates LINE-1 Repetitive Elements

Abstract

Summary: In mammals, LINE-1 (L1) retrotransposons constitute between 15% and 20% of the genome. Although only a few copies have retained the ability to retrotranspose, evidence in brain and differentiating pluripotent cells indicates that L1 retrotransposition occurs and creates mosaics in normal somatic tissues. The function of de novo insertions remains to be understood. The transdifferentiation of mouse embryonic fibroblasts to dopaminergic neuronal fate provides a suitable model for studying L1 dynamics in a defined genomic and unaltered epigenomic background. We found that L1 elements are specifically re-expressed and mobilized during the initial stages of reprogramming and that their insertions into specific acceptor loci coincides with higher chromatin accessibility and creation of new transcribed units. Those events accompany the maturation of neuronal committed cells. We conclude that L1 retrotransposition is a non-random process correlating with chromatin opening and lncRNA production that accompanies direct somatic cell reprogramming. : In this article, Orlando and colleagues show that LINE-1 elements are reactivated and retrotransposed upon transdifferentiation of MEF cells into induced dopaminergic neurons (iDA). The inhibition of LINE-1 elements impairs the transdifferentiation potential of MEF cells. LINE-1 retrotransposition in post-mitotic iDA cells is lineage specific and correlates with chromatin opening and lncRNA production in intergenic genomic regions. Keywords: LINE-1 elements, cell transdifferentiation, cell plasticity