The Autoimmune Regulator (AIRE) Gene, the Master Activator of Self-Antigen Expression in the Thymus

Giraud, Matthieu; Peterson, Pärt

doi:10.1007/978-3-030-12040-5_7

Cited by 7 publications

(12 citation statements)

References 114 publications

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“…One of the main controllers of PGE in mTECs is the autoimmune regulator (Aire) gene, which encodes the AIRE protein that acts as a noncanonical transcription factor that promotes the expression of tissue-restricted antigens (TRAs) [6][7][8][9]. According to Takaba et al [10] 28.9% of the TRAs expressed in mTECs are under the control of Aire and are referred to as Aire-dependent genes.…”

Section: Introductionmentioning

confidence: 99%

miR-155 exerts posttranscriptional control of autoimmune regulator (Aire) and tissue-restricted antigen genes in medullary thymic epithelial cells

et al. 2021

Preprint

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Background: The autoimmune regulator (Aire) gene is critical for the appropriate establishment of central immune tolerance. As one of the main controllers of promiscuous gene expression in the thymus, Aire promotes the expression of thousands of downstream tissue-restricted antigen (TRA) genes, cell adhesion genes and transcription factor genes in medullary thymic epithelial cells (mTECs). Despite the increasing knowledge about the role of Aire as an upstream transcriptional controller, little is known about the mechanisms by which this gene could be regulated. Results: Here, we assessed the posttranscriptional control of Aire by miRNAs. The in silico miRNA-mRNA interaction analysis predicted thermodynamically stable hybridization between the 3UTR of Aire mRNA and miR-155, which was confirmed to occur within the cellular milieu through a luciferase reporter assay. This finding enabled us to hypothesize that miR-155 might play a role as an intracellular posttranscriptional regulator of Aire mRNA. To test this hypothesis, we transfected a murine mTEC cell line with a miR-155 mimic in vitro, which reduced the mRNA and protein levels of Aire. Moreover, large-scale transcriptome analysis showed the modulation of 311 downstream mRNAs, which included 58 TRA mRNAs. Moreover, miR-155 mimic-transfected cells exhibited a decrease in their chemotaxis property compared with control thymocytes. Conclusion: Overall, the results indicate that miR-155 may posttranscriptionally control Aire mRNA as well as a crucial process by which mTECs allow migration of thymocytes through chemotaxis.

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Section: Introductionmentioning

confidence: 99%

miR-155 exerts posttranscriptional control of autoimmune regulator (Aire) and tissue-restricted antigen genes in medullary thymic epithelial cells

et al. 2021

Preprint

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“…The human AIRE gene maps on chromosome 21q22.3 and in the mouse on chromosome 10 position 39.72 cM and the primary structure of Aire gene suggests that the distribution of its domains encodes a protein that interacts with the chromatin and regulates transcriptional processes (2,(20)(21)(22)(23)(24)(25)(26)(27).…”

Section: Introductionmentioning

confidence: 99%

Aire Gene Influences the Length of the 3′ UTR of mRNAs in Medullary Thymic Epithelial Cells

et al. 2020

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Aire is a transcriptional controller in medullary thymic epithelial cells (mTECs) modulating a set of peripheral tissue antigens (PTAs) and non-PTA mRNAs as well as miRNAs. Even miRNAs exerting posttranscriptional control of mRNAs in mTECs, the composition of miRNA-mRNA networks may differ. Under reduction in Aire expression, networks exhibited greater miRNA diversity controlling mRNAs. Variations in the number of 3'UTR binding sites of Aire-dependent mRNAs may represent a crucial factor that influence the miRNA interaction. To test this hypothesis, we analyzed through bioinformatics the length of 3'UTRs of a large set of Aire-dependent mRNAs. The data were obtained from existing RNA-seq of mTECs of wild type or Aire-knockout (KO) mice. We used computational algorithms as FASTQC, STAR and HTSEQ for sequence alignment and counting reads, DESEQ2 for the differential expression, 3USS for the alternative 3'UTRs and TAPAS for the alternative polyadenylation sites. We identified 152 differentially expressed mRNAs between these samples comprising those that encode PTAs as well as transcription regulators. In Aire KO mTECs, most of these mRNAs featured an increase in the length of their 3'UTRs originating additional miRNA binding sites and new miRNA controllers. Results from the in silico analysis were statistically significant and the predicted miRNA-mRNA interactions were thermodynamically stable. Even with no in vivo or in vitro experiments, they were adequate to show that lack of Aire in mTECs might favor the downregulation of PTA mRNAs and transcription regulators via miRNA control. This could unbalance the overall transcriptional activity in mTECs and thus the self-representation.

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“…Um dos principais controladores da PGE nas mTECs é o gene Aire (Autoimmune Regulator), que codifica a proteína AIRE, que atua como um fator de transcrição não canônico promovendo a expressão de diversos TRAs (ANDERSON & SU, 2016, MATHIS & BENOIST, 2007, KYEWSKI & DERBINSKI, 2004GIRAUD & PETERSON, 2019 (Takaba et al, 2015) O gene Aire é expresso em apenas alguns tecidos, mas em sua maioria no timo e mais especificamente em mTECs (ANDERSON et al, 2002). Além disso apenas uma subpopulação de mTECs maduras com fenótipo CD80 hi MHC-II hi , expressam o gene, chamada de mTEC hi Aire + (SANSOM et al, 2014, ST-PIERRE et al, 2015.…”

Section: Aire E a Pgeunclassified

“…A descoberta de Aire como um fator de transcrição não canônico da PGE se deu através do estudo de uma doença autoimune sistêmica chamada de poliendocrinopatia autoimune tipo 1 (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy -APECED) (BRUSERUD et al, 2016, PETERSON et al, 2004GIRAUD & PETERSON, 2019). A APECED é uma doença monogênica autossômica recessiva com sintomas devastadores nos pacientes.…”

Section: Descoberta Do Gene Aireunclassified

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Controle Pós-Transcricional do Gene Autoimmune Regulator (Aire) por meio do microRNA-155

Tanaka¹

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The Autoimmune Regulator (AIRE) Gene, the Master Activator of Self-Antigen Expression in the Thymus

Cited by 7 publications

References 114 publications

miR-155 exerts posttranscriptional control of autoimmune regulator (Aire) and tissue-restricted antigen genes in medullary thymic epithelial cells

miR-155 exerts posttranscriptional control of autoimmune regulator (Aire) and tissue-restricted antigen genes in medullary thymic epithelial cells

Aire Gene Influences the Length of the 3′ UTR of mRNAs in Medullary Thymic Epithelial Cells

Controle Pós-Transcricional do Gene Autoimmune Regulator (Aire) por meio do microRNA-155

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