Sepsis Induces Age- and Sex-Specific Chromatin Remodeling in Myeloid-derived Suppressor Cells

Charles, A. M.; Darden, D. B.; Rodhouse, C. E.; Hernandez-Rios, M.; Gauthier, M.-P. L.; Brant, J. O.; Bacher, R. L.; Mathews, C. E.; Moldawer, L. L.; Efron, P. A.; Maile, R.; Kladde, M. P.

doi:10.1101/2025.05.26.656229

bioRxiv · 10.1101/2025.05.26.656229

Sepsis Induces Age- and Sex-Specific Chromatin Remodeling in Myeloid-derived Suppressor Cells

Charles, A. M.·Darden, D. B.·Rodhouse, C. E.·Hernandez-Rios, M.·Gauthier, M.-P. L.·Brant, J. O.·Bacher, R. L.·Mathews, C. E.·Moldawer, L. L.·Efron, P. A.·Maile, R.·Kladde, M. P.

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Abstract

Sepsis survivors frequently develop long-term immune dysfunction, but the epigenetic mechanisms underlying persistent myeloid suppression remain unclear. Myeloid-derived suppressor cells (MDSCs), whose function is shaped by host age and sex, are key contributors to post-sepsis immune dysregulation. Here, we present a high-resolution epigenetic map targeting gene promoters of MDSCs after sepsis using MAPit-FENGC, a single-molecule assay that simultaneously profiles DNA methylation and chromatin accessibility. In a clinically relevant murine model including young and older adult male and female mice, splenic MDSCs were isolated for MAPit-FENGC and single-cell RNA sequencing. Unsupervised clustering identified nine promoter classes reflecting chromatin dynamics: age- and sex-dependent sepsis-induced opening (Classes 1-4), persistent closure with varying levels of DNA methylation (Classes 5-7), and constitutive openness post-sepsis (Classes 8, 9). Transcriptomic profiling corroborated these promoter states, linking accessibility with gene expression. These findings establish how epigenetic reprogramming of MDSCs may shape age- and sex-specific immune trajectories in sepsis survivors.

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Charles, A. M., Darden, D. B., Rodhouse, C. E., Hernandez-Rios, M., Gauthier, M.-P. L., Brant, J. O., Bacher, R. L., Mathews, C. E., Moldawer, L. L., Efron, P. A., Maile, R., Kladde, M. P.. 2025-05-30. Sepsis Induces Age- and Sex-Specific Chromatin Remodeling in Myeloid-derived Suppressor Cells. https://doi.org/10.1101/2025.05.26.656229

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