Ionizing radiations (IR) alter hematopoietic stem cell (HSC) function on the long term, but the mechanisms underlying these effects are still poorly understood. We recently showed that IR induces the derepression of L1Md, the mouse young subfamilies of LINE-1/L1 retroelements. L1 contributes to gene regulatory networks. However, how L1Md are derepressed and impact HSC gene expression are not known. Here, we show that IR triggers genome-wide H3K9me3 decrease that occurs mainly at L1Md. Loss of H3K9me3 at intronic L1Md harboring NF-κB binding sites motifs but not at promoters is associated with the repression of HSC-specific genes. This is correlated with reduced NFKB1 repressor expression. TNF-α treatment rescued all these effects and prevented IR-induced HSC loss of function in vivo. This TNF-α/NF-κB/H3K9me3/L1Md axis might be important to maintain HSCs while allowing expression of immune genes during myeloid regeneration or damage-induced bone marrow ablation.

Understanding how ionizing radiations (IR) alter hematopoietic stem cell (HSC) function on the long-term is crucial. We recently showed a link between derepression of L1Md, the mouse young subfamilies of LINE-1/L1 retroelements, and IR-induced HSC injury. L1 contribute to gene regulatory networks. However, the mechanisms involved in IR-induced L1Md derepression, and their impact on HSC transcriptome remain to be addressed. Here we show that IR triggers genome-wide H3K9me3 decreased and transcriptomic changes in HSCs, characterized by a loss of the TNF-α/NF-κB and HSC signatures. HSC gene repression is associated to H3K9me3 loss at specific intronic L1Md displaying NF-κB binding sites. This is correlated with reduced NFKB1 repressor expression. TNF-α treatment before IR rescued all these effects and prevented IR-induced HSC loss of function in vivo. This reveals the importance of the TNF-α/NF-κB pathway to control H3K9me3 levels at selected intronic L1Md and thereby preserve HSC gene expression and function during IR stress.