Transcriptomic diversity in human medullary thymic epithelial cells

Jason A. Carter, Léonie Strömich, Matthew Peacey, Sarah R. Chapin, Lars Velten, Lars M. Steinmetz, Benedikt Brors, Sheena Pinto and Hannah V. Meyer ()
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Jason A. Carter: Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory
Léonie Strömich: German Cancer Research Center
Matthew Peacey: School of Biological Sciences, Cold Spring Harbor Laboratory
Sarah R. Chapin: Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory
Lars Velten: The Barcelona Institute of Science and Technology
Lars M. Steinmetz: European Molecular Biology Laboratory, Genome Biology Unit
Benedikt Brors: German Cancer Research Center
Sheena Pinto: German Cancer Research Center
Hannah V. Meyer: Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract The induction of central T cell tolerance in the thymus depends on the presentation of peripheral self-epitopes by medullary thymic epithelial cells (mTECs). This promiscuous gene expression (pGE) drives mTEC transcriptomic diversity, with non-canonical transcript initiation, alternative splicing, and expression of endogenous retroelements (EREs) representing important but incompletely understood contributors. Here we map the expression of genome-wide transcripts in immature and mature human mTECs using high-throughput 5’ cap and RNA sequencing. Both mTEC populations show high splicing entropy, potentially driven by the expression of peripheral splicing factors. During mTEC maturation, rates of global transcript mis-initiation increase and EREs enriched in long terminal repeat retrotransposons are up-regulated, the latter often found in proximity to differentially expressed genes. As a resource, we provide an interactive public interface for exploring mTEC transcriptomic diversity. Our findings therefore help construct a map of transcriptomic diversity in the healthy human thymus and may ultimately facilitate the identification of those epitopes which contribute to autoimmunity and immune recognition of tumor antigens.

Date: 2022
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DOI: 10.1038/s41467-022-31750-1

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