Thymic epithelia amplify noise in chromatin accessibility via p53 repression to impose immune tolerance

Phenotypic plasticity of somatic cells is a principal feature of vertebrate adaptation as well as a hallmark of tumorigenesis. However, the determinants and mechanisms that regulate the stability of somatic cell identities remain unclear. Here, using the somatic plasticity of thymic epithelial cells – which facilitates the selection of a self-discriminating T cell repertoire – as a physiological model system, we show that stochastic fluctuations in background chromatin accessibility at nucleosome-dense regions are amplified by thymic epithelial cells to ectopically express thousands of genes highly restricted to other specialized cell types. We found broad regions of inaccessible chromatin flanking tissue-specific genes become ‘destabilized’ during thymic epithelial maturation independently of AIRE-induced transcription of these genes, but concurrently with the repression of the tumor suppressor p53. Augmenting p53 activity in thymic epithelial cells reduced noise in chromatin accessibility at nucleosome-dense regions, inhibited ectopic expression of tissue-specific genes and caused multi-organ autoimmunity. Furthermore, we found p53-regulated fluctuations in background chromatin accessibility in lung adenocarcinoma to be associated with high plasticity states that promote tumor progression. Taken together, our findings establish p53-dependent stabilization of nucleosomal barriers to cellular reprogramming as a fulcrum of cell fate integrity that underlies critical components of immune tolerance induction and oncogenic potential.