Gene regulatory logic underlying the differentiation of mixed lineages in human thymic epithelial cells
- 1Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
Abstract
The thymus enacts central tolerance through thymic (TECs), which present self-antigens to developing T cells self-reactive cells, preventing autoimmunity. Human TECs include populations that express lineage-committed programs corresponding to distinct peripheral tissues, yet how they acquire these programs and whether these TEC subpopulations are genetically related and conserved in mice remain unknown. Using matched single-cell gene-expression and chromatin-accessibility profiling of 126,687 human TECs, we identified 17 TEC subsets defined by their distinct expression profiles of 1,843 cell type restricted-antigens (CRAs) from 48 peripheral cell types. With a new phylogenetic reconstruction method, we show that lineage-committed TECs share a common ancestor, retain a thymus-specific mixed identity through co-expression of multiple CRA signatures, and are specified by coordinated activator and repressor regulons. We also identified a basement-membrane-collagen-rich state (BMC-TECs) with progenitor-like properties. Finally, mouse TECs shared the regulatory strategy but conserved few master transcription-factor drivers. This study mechanistically characterizes human TEC subpopulations and reveals the gene regulatory logic that leads to their distinct diversification and mixed identities in humans and mice.
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BibTeX
@misc{prabakar2026gene,
title = {{Gene regulatory logic underlying the differentiation of mixed lineages in human thymic epithelial cells}},
author = {R. K. Prabakar and S. R. Chapin and Y. Lin and S. J. Staklinski and D. M. Netz and M. E. Lapine and D. Pruss and T. Cvetanovic and S. L. Carcy and J. Torres and A. Grosh and A. J. Kiedrowski and H. I. Pass and R. Mosca and C. Regan and J. Preall and A. Siepel and H. V. Meyer},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.29.762771},
url = {https://www.biorxiv.org/content/10.64898/2026.10.29.762771v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Gene regulatory logic underlying the differentiation of mixed lineages in human thymic epithelial cells
AU - R. K. Prabakar
AU - S. R. Chapin
AU - Y. Lin
AU - S. J. Staklinski
AU - D. M. Netz
AU - M. E. Lapine
AU - D. Pruss
AU - T. Cvetanovic
AU - S. L. Carcy
AU - J. Torres
AU - A. Grosh
AU - A. J. Kiedrowski
AU - H. I. Pass
AU - R. Mosca
AU - C. Regan
AU - J. Preall
AU - A. Siepel
AU - H. V. Meyer
PY - 2026
DA - 2026/10/29
PB - bioRxiv
DO - 10.64898/2026.10.29.762771
UR - https://www.biorxiv.org/content/10.64898/2026.10.29.762771v1
AB - The thymus enacts central tolerance through thymic (TECs), which present self-antigens to developing T cells self-reactive cells, preventing autoimmunity. Human TECs include populations that express lineage-committed programs corresponding to distinct peripheral tissues, yet how they acquire these programs and whether these TEC subpopulations are genetically related and conserved in mice remain unknown. Using matched single-cell gene-expression and chromatin-accessibility profiling of 126,687 human TECs, we identified 17 TEC subsets defined by their distinct expression profiles of 1,843 cell type restricted-antigens (CRAs) from 48 peripheral cell types. With a new phylogenetic reconstruction method, we show that lineage-committed TECs share a common ancestor, retain a thymus-specific mixed identity through co-expression of multiple CRA signatures, and are specified by coordinated activator and repressor regulons. We also identified a basement-membrane-collagen-rich state (BMC-TECs) with progenitor-like properties. Finally, mouse TECs shared the regulatory strategy but conserved few master transcription-factor drivers. This study mechanistically characterizes human TEC subpopulations and reveals the gene regulatory logic that leads to their distinct diversification and mixed identities in humans and mice.
ER -