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

doi:10.1016/j.stemcr.2019.12.002

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 journal › Article › peer-review

15 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 language	English (US)
Pages (from-to)	60-74
Number of pages	15
Journal	Stem Cell Reports
Volume	14
Issue number	1
DOIs	https://doi.org/10.1016/j.stemcr.2019.12.002
State	Published - 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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10.1016/j.stemcr.2019.12.002

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title = "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.",

keywords = "cell plasticity, cell transdifferentiation, LINE-1 elements",

author = "{Della Valle}, Francesco and Thimma, {Manjula P.} and Massimiliano Caiazzo and Salvatore Pulcrano and Mirko Celii and Adroub, {Sabir A.} and Peng Liu and Gregorio Alanis-Lobato and Vania Broccoli and Valerio Orlando",

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: {\textcopyright} 2019 The Authors",

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doi = "10.1016/j.stemcr.2019.12.002",

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AU - Thimma, Manjula P.

AU - Caiazzo, Massimiliano

AU - Pulcrano, Salvatore

AU - Celii, Mirko

AU - Adroub, Sabir A.

AU - Liu, Peng

AU - Alanis-Lobato, Gregorio

AU - Broccoli, Vania

AU - Orlando, Valerio

N1 - 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

PY - 2020/1/14

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N2 - 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.

AB - 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.

KW - cell plasticity

KW - cell transdifferentiation

KW - LINE-1 elements

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AN - SCOPUS:85077650801

SN - 2213-6711

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EP - 74

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 1

ER -

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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