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

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.

journal_name

J Autoimmun

journal_title

Journal of autoimmunity

authors

Rattay K,Meyer HV,Herrmann C,Brors B,Kyewski B

doi

10.1016/j.jaut.2015.10.001

subject

Has Abstract

pub_date

2016-02-01 00:00:00

pages

65-75

eissn

0896-8411

issn

1095-9157

pii

S0896-8411(15)30046-9

journal_volume

67

pub_type

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