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

Francesco Della Valle, Manjula P. Thimma, Massimiliano Caiazzo, Salvatore Pulcrano, Mirko Celii, Sabir A. Adroub, Peng Liu, Gregorio Alanis-Lobato, Vania Broccoli, Valerio Orlando*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)60-74
Number of pages15
JournalStem Cell Reports
Volume14
Issue number1
DOIs
StatePublished - Jan 14 2020

Bibliographical note

Funding Information:
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.

Funding Information:
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 Copyright:
© 2019 The Authors

Keywords

  • cell plasticity
  • cell transdifferentiation
  • LINE-1 elements

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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