Biologically indeterminate yet ordered promiscuous gene expression in single medullary thymic epithelial cells
| Autor: | Stefano Maio, Jeanette Baran-Gale, Chris P. Ponting, Fatima Dhalla, Lia Chappell, Georg A. Holländer |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
central T‐cell tolerance
Medullary cavity Immunology Thymus Gland autoimmune regulator Biology Chromatin Epigenetics Genomics & Functional Genomics Article General Biochemistry Genetics and Molecular Biology Biological pathway Transcriptome Negative selection Mice 03 medical and health sciences 0302 clinical medicine Antigen thymus Gene expression Animals promiscuous gene expression Molecular Biology Gene 030304 developmental biology medullary thymic epithelial cells Mice Inbred BALB C 0303 health sciences General Immunology and Microbiology Gene Expression Profiling General Neuroscience TSPAN8 Cell Differentiation Epithelial Cells Articles Autoimmune regulator Cell biology Mice Inbred C57BL Organ Specificity Female Single-Cell Analysis Indeterminate Biomarkers 030217 neurology & neurosurgery 030215 immunology |
| Zdroj: | Dhalla, F, Baran-Gale, J, Maio, S, Chappell, L, Holländer, G A & Ponting, C P 2020, ' Biologically indeterminate yet ordered promiscuous gene expression in single medullary thymic epithelial cells ', EMBO Journal, vol. 39, e101828 . https://doi.org/10.15252/embj.2019101828 The EMBO Journal |
| DOI: | 10.1101/554899 |
| Popis: | To induce central T‐cell tolerance, medullary thymic epithelial cells (mTEC) collectively express most protein‐coding genes, thereby presenting an extensive library of tissue‐restricted antigens (TRAs). To resolve mTEC diversity and whether promiscuous gene expression (PGE) is stochastic or coordinated, we sequenced transcriptomes of 6,894 single mTEC, enriching for 1,795 rare cells expressing either of two TRAs, TSPAN8 or GP2. Transcriptional heterogeneity allowed partitioning of mTEC into 15 reproducible subpopulations representing distinct maturational trajectories, stages and subtypes, including novel mTEC subsets, such as chemokine‐expressing and ciliated TEC, which warrant further characterisation. Unexpectedly, 50 modules of genes were robustly defined each showing patterns of co‐expression within individual cells, which were mainly not explicable by chromosomal location, biological pathway or tissue specificity. Further, TSPAN8+ and GP2+ mTEC were randomly dispersed within thymic medullary islands. Consequently, these data support observations that PGE exhibits ordered co‐expression, although mechanisms underlying this instruction remain biologically indeterminate. Ordered co‐expression and random spatial distribution of a diverse range of TRAs likely enhance their presentation and encounter with passing thymocytes, while maintaining mTEC identity. Single‐cell RNA sequencing reveals transcriptional heterogeneity based on both ordered and stochastic elements that enables a dedicated cell population to mirror the body's full self‐antigen complement for development of central T‐cell tolerance. |
| Databáze: | OpenAIRE |
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