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Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration.

Published version
Peer-reviewed

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Authors

Polyzou, Aikaterini 
Prater, Pia 
Sagar 
Morales-Hernández, Antonio 

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.

Description

Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265


Funder: Max-Planck-Gesellschaft (Max Planck Society); doi: https://doi.org/10.13039/501100004189

Keywords

Animals, Cell Proliferation, Cellular Senescence, Chromatin Assembly and Disassembly, DNA Transposable Elements, Endogenous Retroviruses, Enzyme Activation, HEK293 Cells, Hematopoiesis, Hematopoietic Stem Cells, Humans, Interferon-Induced Helicase, IFIH1, Ligands, Long Interspersed Nucleotide Elements, Mice, Inbred C57BL, Mice, Knockout, Myeloablative Agonists, Signal Transduction, Mice

Journal Title

Nat Cell Biol

Conference Name

Journal ISSN

1465-7392
1476-4679

Volume Title

23

Publisher

Springer Science and Business Media LLC
Sponsorship
Deutsche Forschungsgemeinschaft (German Research Foundation) (GRK2344, GRK2344, CIBSS-EXC-2189-Project ID 390939984)
Fritz Thyssen Stiftung (Fritz Thyssen Foundation) (Az 10.17.1.026MN)