FOXO3 induces chromatin changes in a model of DNA damage-induced senescence

FOXO transcription factors are critical for cellular homeostasis and the stress response and have been implicated in longevity in several species. Yet, how these factors function at the chromatin level in differing conditions in human cells is poorly understood. Here, we take an integrated multi-omics approach to identify the chromatin-level mechanisms by which FOXO3 coordinates transcriptional programs in replicating cells and in a model of cellular senescence. In a DNA-damage induced senescence, FOXO3 levels are elevated early in senescence entry. Increased FOXO3 expression induces expression of chromatin remodeling factors, and impacts chromatin accessibility across the genome together with SWI/SNF chromatin remodelers. As cells enter DNA-damage induced senescence, FOXO3 is essential for chromatin remodeling and reprogramming of a genomic network that functions to modulate cell stress and lineage-specific cellular functions. Altogether, we identify a FOXO3-SWI/SNF network that regulates key cellular processes including metabolism, proteostasis, epigenetics, and cell lineage, and is dynamically controlled under DNA damaging conditions.