Chromatin accessibility profiling of IMR-90 SV40-T cells expressing wild-type and mutant H2B

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.