Trends Immunol. 2025 Nov 6:S1471-4906(25)00248-0. doi: 10.1016/j.it.2025.10.004. Online ahead of print.

ABSTRACT

Trained immunity (TRIM) is a de facto form of innate immune memory. While histone modifications contribute to TRIM, their reversible nature and susceptibility to dilution during cell division cannot fully account for its long-term persistence. Here, we propose that DNA methylation patterns, particularly hypomethylation at proinflammatory gene loci, could serve as a key epigenetic mechanism contributing to long-term TRIM. Mechanistically, these hypomethylated states are biochemically stable and faithfully inherited through cell division, acting as a permissive scaffold that enables the rapid accumulation of activating histone marks upon restimulation. This DNA-methylation-mediated process could underpin the durability of TRIM across multiple contexts, including hematopoietic stem cell self-renewal, differentiation from central to peripheral compartments, and autonomy of tissue-resident cells.

PMID:41203534 | DOI:10.1016/j.it.2025.10.004