Thymic epithelial cells amplify epigenetic noise to promote immune tolerance

Noah Gamble, Jason A. Caldwell, Joshua McKeever, Caroline Kaiser, Alexandra Bradu, Peyton J. Dooley, Sandy Klemm, William J. Greenleaf, Narutoshi Hibino, Aaron R. Dinner and Andrew S. Koh ()
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Noah Gamble: University of Chicago
Jason A. Caldwell: University of Chicago
Joshua McKeever: University of Chicago
Caroline Kaiser: University of Chicago
Alexandra Bradu: University of Chicago
Peyton J. Dooley: University of Chicago
Sandy Klemm: Stanford University
William J. Greenleaf: Stanford University
Narutoshi Hibino: University of Chicago
Aaron R. Dinner: University of Chicago
Andrew S. Koh: University of Chicago

Nature, 2025, vol. 646, issue 8085, 724-733

Abstract: Abstract Cellular plasticity is a principal feature of vertebrate adaptation, tissue repair and tumorigenesis1,2. However, the mechanisms that regulate the stability of somatic cell fates remain unclear. Here, we use the somatic plasticity of thymic epithelial cells, which facilitates the selection of a self-discriminating T cell repertoire3, as a physiological model system to show that fluctuations in background chromatin accessibility in nucleosome-dense regions are amplified during thymic epithelial maturation for the ectopic expression of genes restricted to other specialized cell types. This chromatin destabilization was not dependent on AIRE-induced transcription but was preceded by repression of the tumour suppressor p53. Augmenting p53 activity indirectly stabilized chromatin, inhibited ectopic transcription, limited cellular plasticity and caused multi-organ autoimmunity. Genomic regions with heightened chromatin accessibility noise were selectively enriched for nucleosome-destabilizing polymeric AT tracts and were associated with elevated baseline DNA damage and transcriptional initiation. Taken together, our findings define molecular levers that modulate cell fate integrity and are used by thymic epithelial cells for immunological tolerance.

Date: 2025
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DOI: 10.1038/s41586-025-09424-x

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