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  Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration

Clapes, T., Polyzou, A., Prater, P., Sagar, Morales-Hernández, A., Ferrarini, M. G., et al. (2021). Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration. Nature Cell Biology, 23, 704-717. doi:10.1038/s41556-021-00707-9.

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This paper was originally published under standard Springer Nature license (© The Author(s), under exclusive licence to Springer Nature America, Inc.). It is now available as an open-access paper under a Creative Commons Attribution 4.0 International license, © The Author(s). The error has been corrected in the online version of the article.
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 Creators:
Clapes, Thomas1, Author              
Polyzou, Aikaterini1, Author
Prater, Pia1, Author
Sagar2, Author
Morales-Hernández, Antonio3, Author
Ferrarini, Mariana Galvao3, Author
Kehrer, Natalie1, Author
Lefkopoulos, Stylianos1, Author
Bergo, Veronica1, Author
Hummel, Barbara2, Author
Obier, Nadine1, Author
Maticzka, Daniel3, Author
Bridgeman, Anne3, Author
Herman, Josip S.2, Author
Ilik, Ibrahim4, Author
Klaeylé, Lhéanna1, Author
Rehwinkel, Jan3, Author
McKinney-Freeman, Shannon3, Author
Backofen, Rolf3, Author
Akhtar, Asifa4, Author              
Cabezas-Wallscheid, Nina1, Author              Sawarkar, Ritwick2, Author              Rebollo, Rita3, AuthorGrün, Dominic2, Author              Trompouki, Eirini1, Author               more..
Affiliations:
1Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243641              
2Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243642              
3External Organizations, ou_persistent22              
4Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society, ou_2243643              

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Free keywords: Haematopoiesis, Haematopoietic stem cells, Quiescence, Regeneration
 Abstract: Haematopoietic stem cells (HSCs) are normally quiescent, but have evolved mechanisms to respond to stress. Here, we evaluate haematopoietic regeneration induced by chemotherapy. We detect robust chromatin reorganization followed by increased transcription of transposable elements (TEs) during early recovery. TE transcripts bind to and activate the innate immune receptor melanoma differentiation-associated protein 5 (MDA5) that generates an inflammatory response that is necessary for HSCs to exit quiescence. HSCs that lack MDA5 exhibit an impaired inflammatory response after chemotherapy and retain their quiescence, with consequent better long-term repopulation capacity. We show that the overexpression of ERV and LINE superfamily TE copies in wild-type HSCs, but not in Mda5−/− HSCs, results in their cycling. By contrast, after knockdown of LINE1 family copies, HSCs retain their quiescence. Our results show that TE transcripts act as ligands that activate MDA5 during haematopoietic regeneration, thereby enabling HSCs to mount an inflammatory response necessary for their exit from quiescence.

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Language(s): eng - English
 Dates: 2021-07-12
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s41556-021-00707-9
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Title: Nature Cell Biology
  Other : 'Nat. Cell Biol.'
Source Genre: Journal
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Publ. Info: London : Springer Nature
Pages: - Volume / Issue: 23 Sequence Number: - Start / End Page: 704 - 717 Identifier: ISSN: 1465-7392
CoNE: https://pure.mpg.de/cone/journals/resource/954925625310