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

Abstract
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.

Citation
Della Valle, F., Thimma, M. P., Caiazzo, M., Pulcrano, S., Celii, M., Adroub, S. A., … Orlando, V. (2020). Transdifferentiation of Mouse Embryonic Fibroblasts into Dopaminergic Neurons Reactivates LINE-1 Repetitive Elements. Stem Cell Reports, 14(1), 60–74. doi:10.1016/j.stemcr.2019.12.002

Acknowledgements
We are grateful to Fred Gage (Salk Institute) for the L1-EGFP Plasmid and stimulating discussions. John Goodier for pGF21 and pTN201 plasmids. Edith Heard for pTNC7 plasmid. V.O. is supported by King Abdullah University of Science and Technology (BAS 1037/01-01, CRG URF 126310101). M.C. is supported by Italian Ministry of University and Education grant MIUR FIR 2013 RBFR13LH4X_002. V.B. is supported by Italian Ministry of University and Education, Italian Institute of Technology Seed project, Telethon Foundation, Cariplo Foundation, and Michael Fox Foundation and ERC grant AdERC #340527. Thanks to Dr. Giancarlo Bellenchi for sharing reagents and laboratory facilities.

Publisher
Elsevier BV

Journal
Stem cell reports

DOI
10.1016/j.stemcr.2019.12.002

Additional Links
https://linkinghub.elsevier.com/retrieve/pii/S2213671119304163http://www.cell.com/article/S2213671119304163/pdf

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