Gene regulatory logic underlying the differentiation of mixed lineages in human thymic epithelial cells

Prabakar, Rishvanth K, Chapin, Sarah R, Lin, Yong, Staklinski, Stephen J, Netz, Deena M, Lapine, Madison E, Pruss, Dominic, Cvetanovic, Todor, Carcy, Salome L, Torres, Joshua, Grosh, Alexander, Kiedrowski, Alexandra J, Pass, Harvey I, Mosca, Ralph, Regan, Claire, Preall, Jonathan, Siepel, Adam, Meyer, Hannah V (November 2026) Gene regulatory logic underlying the differentiation of mixed lineages in human thymic epithelial cells. bioRxiv. ISSN 2692-8205 (Submitted)

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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.

Item Type: Paper
Subjects: bioinformatics
bioinformatics > quantitative biology
organs, tissues, organelles, cell types and functions > organs types and functions
organs, tissues, organelles, cell types and functions
organs, tissues, organelles, cell types and functions > organs types and functions > thymus
CSHL Authors:
Communities: CSHL labs > Koo Lab
CSHL labs > Meyer Lab
CSHL labs > Preall lab
CSHL labs > Siepel lab
CSHL Post Doctoral Fellows
School of Biological Sciences > Publications
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 2 November 2026
Date Deposited: 05 Nov 2026 18:53
Last Modified: 05 Nov 2026 18:53
Related URLs:
URI: https://repository.cshl.edu/id/eprint/42361

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