Evolutionary conserved gene co-expression drives generation of self-antigen diversity in medullary thymic epithelial cells
Promiscuous expression of a plethora of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs) is essential for central tolerance. This promiscuous gene expression (pGE) is characterized by inclusion of a broad range of TRAs and by its mosaic expression patterns, i.e. each an...
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| Hauptverfasser: | , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
[2016]
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| In: |
Journal of autoimmunity
Year: 2016, Jahrgang: 67, Pages: 65-75 |
| ISSN: | 1095-9157 |
| DOI: | 10.1016/j.jaut.2015.10.001 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.jaut.2015.10.001 Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S0896841115300469 
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| Verfasserangaben: | Kristin Rattay, Hannah Verena Meyer, Carl Herrmann, Benedikt Brors, Bruno Kyewski |
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| 520 | |a Promiscuous expression of a plethora of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs) is essential for central tolerance. This promiscuous gene expression (pGE) is characterized by inclusion of a broad range of TRAs and by its mosaic expression patterns, i.e. each antigen is only expressed in 1-3% of mTECs. It is currently unclear to which extent random and/or deterministic mechanisms are involved in the regulation of pGE. In order to address this issue, we deconstructed the transcriptional heterogeneity in mTEC to minor subsets expressing a particular TRA. We identified six delineable co-expression groups in mouse mTECs. These co-expression groups displayed a variable degree of mutual overlap and mapped to different stages of mTEC development. Co-expressed genes showed chromosomal preference and clustered within delimited genomic regions. Moreover, co-expression groups in mice and humans selected by a pair of orthologous genes preferentially co-expressed sets of orthologous genes attesting to the species conservation of pGE between mouse and human. Furthermore, co-expressed genes were enriched for specific transcription factor binding motifs concomitant with up-regulation of the corresponding transcription factors, implicating additional factors in the regulation of pGE besides the Autoimmune Regulator (Aire). Thus promiscuous transcription of self-antigens in mTECs entails a highly coordinated process, which is evolutionary strictly conserved between species. | ||
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| 650 | 4 | |a Medullary thymic epithelial cells | |
| 650 | 4 | |a Promiscuous gene expression | |
| 650 | 4 | |a Tissue-restricted antigen | |
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