Evolutionary conserved gene co-expression drives generation of self-antigen diversity in medullary thymic epithelial cells. (February 2016)

• Record Type: Journal Article
• Authors: Rattay, Kristin; Meyer, Hannah Verena; Herrmann, Carl; Brors, Benedikt; Kyewski, Bruno
• Is Part Of: Journal of autoimmunity. Volume 67(2016)
• Page Start: 65
• Page End: 75
• Publication Date: 2016-02
• Subjects: Promiscuous gene expression -- Tissue-restricted antigen -- Medullary thymic epithelial cells -- Tolerance -- Gene co-expression; pGE promiscuous gene expression -- TRA tissue-restricted antigen -- mTEC medullary thymic epithelial cell -- cTEC cortical thymic epithelial cell -- Aire Autoimmune regulator -- PWMs position weight matrices; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2015.10.001
• Languages: English
• ISSNs: 0896-8411

Abstract

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. Highlights: The mTEC compartment represents a composite of gene co-expression groups. Promiscuous gene expression is a highly coordinated and evolutionary conserved process. Promiscuous gene expression targets genomic regions enriched in tissue-restricted antigens. Gene co-expression groups map to distinct stages of mTEC development.