title: An evolutionarily conserved mutual interdependence between Aire and microRNAs in promiscuous gene expression.
abstract: The establishment and maintenance of central tolerance depends to a large extent on the ability of medullary thymic epithelial cells to express a variety of tissue-restricted antigens, the so-called promiscuous gene expression (pGE). Autoimmune regulator (Aire) is to date the best characterised transcriptional regulator known to at least partially coordinate pGE. There is accruing evidence that the expression of Aire-dependent and -independent genes is modulated by higher order chromatin configuration, epigenetic modifications and post-transcriptional control. Given the involvement of microRNAs (miRNAs) as potent post-transcriptional modulators of gene expression, we investigated their role in the regulation of pGE in purified mouse and human thymic epithelial cells (TECs). Microarray profiling of TEC subpopulations revealed evolutionarily conserved cell type and differentiation-specific miRNA signatures with a subset of miRNAs being significantly upregulated during terminal medullary thymic epithelial cell differentiation. The differential regulation of this subset of miRNAs was correlated with Aire expression and some of these miRNAs were misexpressed in the Aire knockout thymus. In turn, the specific absence of miRNAs in TECs resulted in a progressive reduction of Aire expression and pGE, affecting both Aire-dependent and -independent genes. In contrast, the absence of miR-29a only affected the Aire-dependent gene pool. These findings reveal a mutual interdependence of miRNA and Aire.
authors.affiliation: Division of Developmental Immunology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Ucar
authors.forename: Lars-Oliver
authors.initials: LO
authors.lastname: Tykocinski
authors.forename: James
authors.initials: J
authors.lastname: Dooley
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
authors.forename: Bruno
authors.initials: B
authors.lastname: Kyewski
mesh_terms: D000818:Animals; D002469:Cell Separation; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017634:Self Tolerance / Q000235:genetics* / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism*; D000096927:AIRE Protein
chemical_list: D035683:MicroRNAs; D014157:Transcription Factors; D000096927:AIRE Protein
keywords: Aire; Thymic epithelium; gene expression; microRNA (miRNA)