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 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.
Division of Developmental Immunology, Tumor Immunology Program, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
Kristin
K
Rattay
Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, 69120, Germany.
Hannah Verena
HV
Meyer
Institute of Pharmacy and Molecular Biotechnology, Bioquant Center, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg, 69120, Germany; Division Theoretical Bioinformatics, DKFZ, 69120, Heidelberg, Germany.
Carl
C
Herrmann
Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, 69120, Germany; National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany; German Consortium for Translational Cancer Research (DKTK), 69120, Heidelberg, Germany.
Benedikt
B
Brors
Division of Developmental Immunology, Tumor Immunology Program, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. Electronic address: b.kyewski@dkfz-heidelberg.de.
Bruno
B
Kyewski
D000818:Animals; D001324:Autoantigens / Q000235:genetics* / Q000276:immunology*; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D016000:Cluster Analysis; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D059372:Nucleotide Motifs; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
D001324:Autoantigens; D014157:Transcription Factors
Gene co-expression; Medullary thymic epithelial cells; Promiscuous gene expression; Tissue-restricted antigen; Tolerance