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Transcriptional impact of Aire varies with cell type.

ABSTRACT: Aire promotes T cell tolerance by inducing the expression of a broad swath of genes encoding peripheral tissue antigens (PTAs) in medullary epithelial cells (MECs) of the thymus. The exact mechanism used in inducing this ectopic transcription remains obscure. To address this issue, we generated transgenic mice expressing Aire in pancreatic islet beta cells. Gene-expression profiling of such islets revealed that Aire can have a significant impact on transcription in these cells, mainly inducing, but also repressing, transcript levels in a manner comparable with its influence on MECs. The exact transcripts affected differed in MECs and beta cells, with limited overlap between the two sets of Aire-modulated genes. We propose that Aire promotes ectopic gene expression by a generic mechanism that does not depend on any particular characteristics or transcription mechanisms operating in MECs, whereas the cellular environment does govern which genes are actually susceptible to Aire regulation.

SUBMITTER: Guerau-de-Arellano M

PROVIDER: S-EPMC2544570 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Transcriptional impact of Aire varies with cell type.

Guerau-de-Arellano Mireia M Mathis Diane D Benoist Christophe C

Proceedings of the National Academy of Sciences of the United States of America 20080909 37

Aire promotes T cell tolerance by inducing the expression of a broad swath of genes encoding peripheral tissue antigens (PTAs) in medullary epithelial cells (MECs) of the thymus. The exact mechanism used in inducing this ectopic transcription remains obscure. To address this issue, we generated transgenic mice expressing Aire in pancreatic islet beta cells. Gene-expression profiling of such islets revealed that Aire can have a significant impact on transcription in these cells, mainly inducing, ...[more]

PMID: 18780794

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Project description:BackgroundThe autoimmune regulator (AIRE) is expressed in the thymus, particularly in thymic medullary epithelial cells (mTECs), and is required for the ectopic expression of a diverse range of peripheral tissue antigens by mTECs, facilitating their ability to perform negative selection of auto-reactive immature T-cells. The expression profile of peripheral tissue antigens is affected not only by AIRE deficiency but also with variation of AIRE activity in the thymus.Method and resultsTherefore we screened 591bp upstream of the AIRE transcription start site including AIRE minimal promoter for single nucleotide polymorphism (SNPs) and identified two SNPs -655R (rs117557896) and -230Y (rs751032) respectively. To study the effect of these variations on AIRE promoter activity we generated a Flp-In host cell line which was stably transfected with a single copy of the reporter vector. Relative promoter activity was estimated by comparing the luciferase specific activity for lysates of the different reporter AIRE promoter-reporter gene constructs including AIRE-655G AIRE-230C, AIRE-655G AIRE-230T and AIRE-655A AIRE-230C. The analysis showed that the commonest haplotype AIRE-655G AIRE-230C has the highest luciferase specific activity (p<0.001). Whereas AIRE-655G AIRE-230T has a luciferase specific activity value that approaches null. Both AIRE promoter polymorphic sites have one allele that forms a CpG methylation site which we determined can be methylated in methylation assays using the M.SssI CpG methyltransferase.ConclusionAIRE-230Y is in a conserved region of the promoter and is adjacent to a predicted WT1 transcription factor binding site, suggesting that AIRE-230Y affects AIRE expression by influencing the binding of biochemical factors to this region. Our findings show that AIRE-655GAIRE-230T haplotype could dramatically alter AIRE transcription and so have an effect on the process of negative selection and affect susceptibility to autoimmune conditions.

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Transcriptional impact of Aire varies with cell type.

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Transcriptional impact of Aire varies with cell type.

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