The NF-κB pathway regulates heterochromatin at intronic young LINE-1 elements and hematopoietic stem cell gene expression during irradiation stress

Abstract

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 contribute 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-{kappa}B 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--treatment before IR rescued all these effects and prevented IR-induced HSC loss of function in vivo. This TNF-/NF-{kappa}B/H3K9me3/L1Md axis might be important to maintain of HSCs while allowing expression of immune genes during myeloid regeneration or damage-induced bone marrow ablation.