Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic 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.

cGAS/STING-DEPENDENT SENSING OF ENDOGENOUS RNA

“…As the IFN response in SAMHD1-deficient mice is weak, we propose that loss of cGAS/STING signaling in cells lacking SAMHD1 de-sensitizes the RLR pathways and increases tolerance against RNA ligands, thereby preventing spontaneous induction of IFN despite the presence of an endogenous MDA5 ligand. To this end, dsRNA originating from endogenous retroelements has been shown to activate MDA5 in cells lacking the AGS gene ADAR1 (Ahmad et al, 2018) and after DNA damage induced by chemotherapy (Clapes et al, 2021). De-repression of endogenous retroelements is not only a physiological response (Lima-Junior et al, 2021; Young et al, 2012; Yu et al, 2012) but it is also a general stress-response (Simon et al, 2019; De Cecco et al, 2019), and SAMHD1-deficient cells display signs of replication stress including spontaneous DNA damage as shown here and previously by other groups (Daddacha et al, 2017; Coquel et al, 2018).…”

Integrative analysis ofHydrahead regeneration reveals actions of conserved signaling pathways and transposable elements

“…TEs have been shown to affect chromatin accessibility and even to have post-transcriptional effects thus it is hypothesized that they have a role in pleuripotency (Hackett et al, 2017). In terms of regeneration, increase in TEs were detected in regenerating haematopoietic stem cells and overexpression of TEs led to their activation (Clapes et al, 2021). In the sea cucumber Holothuria glaberrima , it was found that changes in transcription of retrotransposons were associated with tissue regeneration (Mashanov et al, 2012).…”

Endogenous Retroviruses (ERVs): Does RLR (RIG-I-Like Receptors)-MAVS Pathway Directly Control Senescence and Aging as a Consequence of ERV De-Repression?

“…By analyzing the chromatin accessibility and the transcription rate of murine HSCs exposed to 5-FU treatment in vivo , it was observed that some transposable elements mainly belonging to the LINE1, ERV1 and ERVK families were derepressed and activate the RNA sensor MDA5 ( 51 ). This leads to the phosphorylation and activation of IRF3 and to the subsequent activation of interferon and inflammation.…”

“…This leads to the phosphorylation and activation of IRF3 and to the subsequent activation of interferon and inflammation. As a consequence of the activation of a pro-inflammatory state, these HSCs exposed to chemotherapy became more active and allowed the rapid reconstitution of murine blood system; on the opposite Mda5 -/- HSC failed to detect ERVs and maintained a prolonged quiescence state that allows for better long-term bone marrow performance but worse rapid response to stressful conditions such as serial 5-FU treatment ( 51 ). Similarly, ionizing radiations trigger monocyte to macrophage differentiation as a result of the establishment of a pro-inflammatory environment which is due to the significant de-repression of ERVs and their asymmetric and anti-sense privileged transcription and the subsequent activation of the MDA5/MAVS ( 52 ).…”

“…This leads to the polarization of the macrophages toward a pro-inflammatory phenotype that allows their high resistance to radiation, but also the acquisition of oncogenic features ( 52 ). Despite the multiple evidence for an effect of genotoxic agents ( 51 , 52 ) and radiotherapy ( 53 ) in activating the transcription of ERVs, the epigenetic mechanism underlying this phenomenon remains to be elucidated. However, the involvement of ATM kinase is highly plausible ( 53 ).…”