Thymic Cells Enhance Epigenetic Noise to Promote Immune Tolerance

The study reveals that thymic epithelial cells amplify epigenetic noise independently of AIRE, primarily through AT-rich sequences, leading to increased plasticity and ectopic gene expression. This chromatin destabilization is regulated by p53 activity, which suppresses accessibility noise and limits cellular plasticity, thereby maintaining immune tolerance. Enhancing p53 activity reduces this plasticity, but can also cause autoimmunity, and similar mechanisms are observed in cancer models, linking chromatin noise, p53 regulation, and cell fate stability.