Thymic epithelial cells amplify epigenetic noise to promote immune tolerance

Authors

Noah Gamble, Department of Pathology, University of Chicago, Chicago, IL, USA.
Jason A. Caldwell, Department of Pathology, University of Chicago, Chicago, IL, USA.
Joshua McKeever, Department of Pathology, University of Chicago, Chicago, IL, USA.
Caroline Kaiser, Department of Pathology, University of Chicago, Chicago, IL, USA.
Alexandra Bradu, Department of Pathology, University of Chicago, Chicago, IL, USA.
Peyton J. Dooley, Department of Pathology, University of Chicago, Chicago, IL, USA.
Sandy Klemm, Department of Genetics, Stanford University, Stanford, CA, USA.
William J. Greenleaf, Department of Genetics, Stanford University, Stanford, CA, USA.
Narutoshi Hibino, Advocate Health - MidwestFollow
Aaron R. Dinner, Department of Chemistry, University of Chicago, Chicago, IL, USA.
Andrew S. Koh, Department of Pathology, University of Chicago, Chicago, IL, USA. akoh@uchicago.edu.

Recommended Citation

Gamble N, Caldwell JA, McKeever J, Kaiser C, Bradu A, Dooley PJ, Klemm S, Greenleaf WJ, Hibino N, Dinner AR, Koh AS. Thymic epithelial cells amplify epigenetic noise to promote immune tolerance. Nature. 2025 Oct;646(8085):724-733. doi: 10.1038/s41586-025-09424-x. Epub 2025 Aug 20. PMID: 40836089; PMCID: PMC12527919.

Affiliations

Advocate Children's Hospital

Abstract

Cellular plasticity is a principal feature of vertebrate adaptation, tissue repair and tumorigenesis^1,2. 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.

Type

Article

PubMed ID

40836089