Evolutionary conserved gene co-expression drives generation of self-antigen diversity in medullary thymic epithelial cells

• Verfasst von: Rattay, Kristin [VerfasserIn]
• Verfasst von: Meyer, Hannah V. [VerfasserIn]
• Verfasst von: Herrmann, Carl [VerfasserIn]
• Verfasst von: Brors, Benedikt [VerfasserIn]
• Verfasst von: Kyewski, Bruno [VerfasserIn]
• Titel: Evolutionary conserved gene co-expression drives generation of self-antigen diversity in medullary thymic epithelial cells
• Verf.angabe: Kristin Rattay, Hannah Verena Meyer, Carl Herrmann, Benedikt Brors, Bruno Kyewski
• E-Jahr: 2016
• Jahr: [2016]
• Umfang: 11 S.
• Illustrationen: Illustrationen
• Fussnoten: Available online 23 October 2015 ; Gesehen am 17.06.2020
• Titel Quelle: Enthalten in: Journal of autoimmunity
• Ort Quelle: London : Academic Press, 1988
• Band/Heft Quelle: 67(2016), Seite 65-75
• ISSN Quelle: 1095-9157
• DOI: doi:10.1016/j.jaut.2015.10.001
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Gene co-expression
• Sach-SW: Medullary thymic epithelial cells
• Sach-SW: Promiscuous gene expression
• Sach-SW: Tissue-restricted antigen
• Sach-SW: Tolerance
• K10plus-PPN: 1700722395

Abstract

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.