Differential sensitivity to LINE 1-induced damage contributes to the expansion of Tet2-deficient HSCs upon chronic inflammatory stress

Chronic inflammation that accompanies aging impairs the function of hematopoietic stem cells (HSCs) and promotes expansion of TET2 -mutated cells, leading to clonal hematopoiesis of indeterminate potential (CHIP). The molecular mechanisms underlying these processes are still unclear. We recently showed that age and stresses like irradiation reduce the heterochromatin mark H3K9me3, leading to the epigenetic derepression of transposable elements such as LINE-1/L1, and L1-induced HSC functional changes through DNA damage and transcriptomic alterations. However, the impact of TEs on the clonal expansion of Tet2 ^-/- HSCs upon chronic inflammation is unknown. Here we show that in wild type (WT) HSC, chronic inflammation induced by repeated low doses of lipopolysaccharide (LPS) triggers H3K9me3 loss at L1. We further show that L1s are involved in LPS-induced DNA damage and reduction of HSC clonogenicity. In contrast, Tet2 ^-/- HSCs resist LPS-induced L1 epigenetic derepression and associated DNA damage. As a result, WT HSCs show decreased competitiveness against Tet2 ^-/- HSCs upon chronic inflammation. These findings identify epigenetic control of L1s as a key mediator of inflammation-induced HSC dysfunction and clonal expansion of Tet2 -mutant cells.