Overview

• Single-cell analyses of medullary thymic epithelial cells showed pervasive chromatin accessibility variability that lets individual cells activate genes normally restricted to other tissues.
• The cells downregulate p53 before entering this variable state, positioning p53 as a switch between chromatin stability and lability.
• Enhancing p53 activity stabilized chromatin, reduced variability, prevented activation of tissue-specific genes, and allowed self-reactive T cells to escape, producing multi-organ autoimmunity in models.
• In lung cancer models, deleting p53 increased epigenetic variability, expanded genomic sampling, and promoted more aggressive, mixed tissue–program states.
• The team plans to probe whether similar variability operates during wound healing and whether it can be harnessed to reprogram cells for immunotherapy or to address autoimmunity.