Chemotherapy-induced transposable elements activate MDA5 to enhance 
haematopoietic regeneration

Clapes, Thomas; Polyzou, Aikaterini; Prater, Pia; Sagar,; Morales-Hernández, Antonio; Ferrarini, Mariana Galvao; Kehrer, Natalie; Lefkopoulos, Stylianos; Bergo, Veronica; Hummel, Barbara; Obier, Nadine; Maticzka, Daniel; Bridgeman, Anne; Herman, Josip S.; Ilik, Ibrahim; Klaeylé, Lhéanna; Rehwinkel, Jan; McKinney-Freeman, Shannon; Backofen, Rolf; Akhtar, Asifa; Cabezas-Wallscheid, Nina; Sawarkar, Ritwick; Rebollo, Rita; Grün, Dominic; Trompouki, Eirini

doi:10.1038/s41556-021-00707-9

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Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration

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Clapes, Thomas
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Polyzou, Aikaterini
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Prater, Pia
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Sagar,
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Kehrer, Natalie
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Lefkopoulos, Stylianos
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Bergo, Veronica
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Hummel, Barbara
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Obier, Nadine
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Herman, Josip S.
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Ilik, Ibrahim
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Klaeylé, Lhéanna
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons198888

Akhtar, Asifa
Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons204274

Cabezas-Wallscheid, Nina
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons241703

Sawarkar, Ritwick
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons241712

Grün, Dominic
Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

/persons/resource/persons241707

Trompouki, Eirini
Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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https://www.nature.com/articles/s41556-021-00707-9
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Clapes et al. 2021.pdf
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Clapes et al. 2021_publisher corrections.pdf
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Citation

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.

Cite as: https://hdl.handle.net/21.11116/0000-0008-DB67-E

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.