Bulk mRNA-seq analysis of mouse skeletal muscle, heart and liver expressing wild-type and mutant H2B

Nucleosomes are the minimal repeating units of chromatin. Their dynamic assembly and disassembly underpins chromatin organization and genome regulation. However, how intrinsic nucleosome stability contributes to higher-level yet fundamental cellular and organismal properties—such as preservation of cell identity, lineage specification, stress resilience and healthy aging—remains unclear. To address this, we tested the impact of intrinsic nucleosome instability across multiple cell, tissue and organismal models by introducing histone mutants that weaken histone–histone interactions. Despite no overt effects on global chromatin accessibility, DNA damage, steady-state proliferation or cell viability, nucleosome instability impaired lineage-specific gene expression programs, altered lineage specification and activated intrinsic inflammatory and stress pathways in a manner reminiscent of aging in mouse tissues and human cells. Consistently, in Caenorhabditis elegans and Drosophila melanogaster, nucleosome instability accelerated the onset of age-associated transcriptional alterations and functional decline in Caenorhabditis elegans and Drosophila melanogaster, and . At the cellular level, nucleosome instability also heightened cellular sensitivity vulnerability to exogenous perturbations—including environmental, epigenetic and mitotic stress—in human cells and Saccharomyces cerevisiaeyeast. These cross-species findings identify nucleosome stability as an evolutionarily conserved epigenetic safeguard that preserves cell identity and stress resilience, sustaining organismal function and longevity.