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

STOLZ, A.; XUAN, C.; FREITAS, C.; CHELBI, R.; AIT-OUGOURAM, H.; FANDREI, D.; YE, M.; NELSON, E.; MAILLARD, C.; BOHM, M.; EL-CHOUFANI, S.; PORQUET, A.; ZHANG, W.; ISSOULAIENE, K.; MUCHARDT, C.; ZUEVA, E.; GOODHARDT, M.; GARRICK, D.; PORTEU, F.; ELVIRA-MATELOT, E.

doi:10.1101/2025.07.21.665900

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bioRxiv · 10.1101/2025.07.21.665900

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

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Abstract

Chronic inflammation disrupts hematopoietic stem cell (HSC) function and drives the expansion of TET2-mutated clones, fostering clonal hematopoiesis of indeterminate potential (CHIP). However, the molecular mechanisms linking inflammation to these hematopoietic alterations remain poorly understood. Here, we uncover a pivotal role of transposable element (TE) derepression, specifically of the most recent LINE-1 (L1) elements, in mediating inflammation-induced HSC dysfunction. We show that chronic exposure to low-dose lipopolysaccharide (LPS) causes a loss of the heterochromatin mark H3K9me3 at L1s in wild-type (WT) HSCs, leading to L1 activation, DNA damage, and reduced clonogenic capacity. Remarkably, Tet2-/- HSCs are resistant to this LPS-induced L1 derepression and associated genomic instability. Furthermore, targeted degradation of L1 RNAs in WT HSCs diminishes the competitive advantage of Tet2-/- HSCs under chronic inflammatory conditions both in vitro and in vivo. These findings reveal epigenetic control of L1 elements as a previously unrecognized mechanism that links chronic inflammation to HSC impairment and clonal expansion of Tet2-mutant cells. This work highlights TE regulation as a critical determinant of hematopoietic fitness and clonal evolution under inflammatory stress.

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STOLZ, A., XUAN, C., FREITAS, C., CHELBI, R., AIT-OUGOURAM, H., FANDREI, D., YE, M., NELSON, E., MAILLARD, C., BOHM, M., EL-CHOUFANI, S., PORQUET, A., ZHANG, W., ISSOULAIENE, K., MUCHARDT, C., ZUEVA, E., GOODHARDT, M., GARRICK, D., PORTEU, F., ELVIRA-MATELOT, E.. 2025-07-21. Differential sensitivity to LINE 1-induced damage contributes to the expansion of Tet2-deficient HSCs upon chronic inflammatory stress. https://doi.org/10.1101/2025.07.21.665900

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