Overview

• Single-cell profiling of medullary thymic epithelial cells revealed highly variable chromatin accessibility that primes ectopic, tissue-specific gene activation.
• These transient identity shifts enable broad self-antigen display to developing T cells, supporting central tolerance in the thymus.
• Genetically enhancing p53 in these cells stabilized chromatin, reduced epigenetic noise, and prevented activation of tissue-restricted genes.
• Mice with enforced p53 activity in thymic epithelium allowed self-reactive T cells to escape deletion, producing multi-organ autoimmune disease.
• The authors also report that p53 loss in lung cancer permits genome sampling via epigenetic noise linked to more aggressive, alternative tissue programs, and they plan to probe roles in wound repair and therapeutic reprogramming.