Models to explore the molecular function and regulation of AIRE

Lovewell, Thomas; Tazi-Ahnini, Rachid

doi:10.1016/j.ejmhg.2011.06.008

Cited by 2 publications

(2 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since the advent of Aire knockout mice, we have been able to explore the biological effects of Aire at the systemic, tissue, and cellular level and the thymi from these murine models have been used to explore the biochemical properties of Aire, particularly for determining the downstream targets of aire-regulated gene expression (ARGE) ( 5 , 34 – 39 ). Cell line models in many respects are more suited for exploring the molecular mechanisms of AIRE/Aire function, as they are not limited by the number of AIRE + /Aire + cells in a single tissue, can be easily manipulated by chemical and genetic treatments and critically, are the only available option for the study of AIRE in a model system of human origin ( 40 ). Our aim was to determine the human gene targets of ARGE, then, to identify and explore any conserved patterns of expression between our cell line model and murine ARGE data.…”

Section: Introductionmentioning

confidence: 99%

Meta-Analysis of Autoimmune Regulator-Regulated Genes in Human and Murine Models: A Novel Human Model Provides Insights on the Role of Autoimmune Regulator in Regulating STAT1 and STAT1-Regulated Genes

et al. 2018

Self Cite

View full text Add to dashboard Cite

Autoimmune regulator (AIRE) regulates promiscuous expression of tissue-restricted antigens in medullary epithelial cells (mTEC) of the thymus. To understand the diverse effects of AIRE, it is crucial to elucidate the molecular mechanisms underlying the process of AIRE-regulated gene expression. In this study, we generated a recombinant AIRE expression variant of the TEC 1A3 human cell line, TEC 1A3 AIREhi, to determine genes targeted by AIRE, and using microarray analysis, we identified 482 genes showing significant differential expression (P < 0.05; false discovery rate <5%), with 353 upregulated and 129 downregulated by AIRE expression. Microarray data were validated by quantitative PCR, confirming the differential expression of 12 known AIRE-regulated genes. Comparison of AIRE-dependent differential expression in our cell line model with murine datasets identified 447 conserved genes with a number of transcription regulatory interactions, forming several key nodes, including STAT1, which had over 30 interactions with other AIRE-regulated genes. As STAT1 mutations cause dominant chronic mucocutaneous candidiasis and decreased STAT1 levels in monocytes of autoimmune polyglandular syndrome 1 (APS-1) patients, it was important to further characterize AIRE–STAT1 interactions. TEC 1A3AIREhi were treated with the STAT1 phosphorylation inhibitors fludarabine and LLL3 showed that phosphorylated STAT1 (p-STAT1) was not responsible for any of the observed differential expression. Moreover, treatment of TEC 1A3 AIREhi with STAT1 shRNA did not induce any significant variation in the expression of unphosphorylated STAT1 (U-STAT1) downstream genes, suggesting that these genes were directly regulated by AIRE but not via U-STAT1. The novel model system we have developed provides potential opportunities for further analysis of the pathogenesis of (APS-1) and the wider roles of the AIRE gene.

show abstract

Section: Introductionmentioning

confidence: 99%

Meta-Analysis of Autoimmune Regulator-Regulated Genes in Human and Murine Models: A Novel Human Model Provides Insights on the Role of Autoimmune Regulator in Regulating STAT1 and STAT1-Regulated Genes

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Interestingly, SPDF overexpression was shown to suppress intrinsic, innate immune signaling, thereby inhibiting inflammation (Korfhagen et al 2012 ). AIRE is a central protein in maintaining immune tolerance (Huoh et al 2020 ), whose expression was identified at both mRNA and protein levels in renal epithelial cells of tubules and podocytes (Lovewell and Tazi-Ahnini 2011 ). Besides possible adverse effects, its up-regulation might indicate the physiological response of the immune system to the foreign substance.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide DNA methylome and transcriptome changes induced by inorganic nanoparticles in human kidney cells after chronic exposure

et al. 2022

View full text Add to dashboard Cite

The unique physicochemical properties make inorganic nanoparticles (INPs) an exciting tool in diagnosis and disease management. However, as INPs are relatively difficult to fully degrade and excrete, their unintended accumulation in the tissue might result in adverse health effects. Herein, we provide a methylome–transcriptome framework for chronic effects of INPs, commonly used in biomedical applications, in human kidney TH-1 cells. Renal clearance is one of the most important routes of nanoparticle excretion; therefore, a detailed evaluation of nanoparticle-mediated nephrotoxicity is an important task. Integrated analysis of methylome and transcriptome changes induced by INPs (PEG-AuNPs, Fe3O4NPs, SiO2NPs, and TiO2NPs) revealed significantly deregulated genes with functional classification in immune response, DNA damage, and cancer-related pathways. Although most deregulated genes were unique to individual INPs, a relatively high proportion of them encoded the transcription factors. Interestingly, FOS hypermethylation inversely correlating with gene expression was associated with all INPs exposures. Our study emphasizes the need for a more comprehensive investigation of INPs’ biological safety, especially after chronic exposure. Graphical abstract

show abstract

Models to explore the molecular function and regulation of AIRE

Cited by 2 publications

References 83 publications

Meta-Analysis of Autoimmune Regulator-Regulated Genes in Human and Murine Models: A Novel Human Model Provides Insights on the Role of Autoimmune Regulator in Regulating STAT1 and STAT1-Regulated Genes

Meta-Analysis of Autoimmune Regulator-Regulated Genes in Human and Murine Models: A Novel Human Model Provides Insights on the Role of Autoimmune Regulator in Regulating STAT1 and STAT1-Regulated Genes

Genome-wide DNA methylome and transcriptome changes induced by inorganic nanoparticles in human kidney cells after chronic exposure

Contact Info

Product

Resources

About