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Mechanistic dissection of dominant AIRE mutations in mouse models reveals evidence for AIRE auto-regulation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE151013 | GEO | 2021/08/30

REPOSITORIES: GEO

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Mechanistic dissection of dominant AIRE mutations in mouse models reveals evidence for AIRE auto-regulation [RNA-seq]

Project description:Using mouse models of several recessive and putative dominant-negative patient mutations we were able to dissect the mechanisms that underlie the recessive and dominant-negative capacities of the corresponding AIRE mutants, including a newly identified dominant-negative variant C446G We also identify an auto-regulatory mechanism by which AIRE negatively modulates its own expression.

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Mechanistic dissection of dominant AIRE mutations in mouse models reveals evidence for AIRE auto-regulation [ATAC-seq]

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Mechanistic dissection of dominant AIRE mutations in mouse models reveals AIRE autoregulation.

Project description:The autoimmune regulator (AIRE) is essential for the establishment of central tolerance and prevention of autoimmunity. Interestingly, different AIRE mutations cause autoimmunity in either recessive or dominant-negative manners. Using engineered mouse models, we establish that some monoallelic mutants, including C311Y and C446G, cause breakdown of central tolerance. By using RNAseq, ATACseq, ChIPseq, and protein analyses, we dissect the underlying mechanisms for their dominancy. Specifically, we show that recessive mutations result in a lack of AIRE protein expression, while the dominant mutations in both PHD domains augment the expression of dysfunctional AIRE with altered capacity to bind chromatin and induce gene expression. Finally, we demonstrate that enhanced AIRE expression is partially due to increased chromatin accessibility of the AIRE proximal enhancer, which serves as a docking site for AIRE binding. Therefore, our data not only elucidate why some AIRE mutations are recessive while others dominant, but also identify an autoregulatory mechanism by which AIRE negatively modulates its own expression.

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Mechanistic dissection of dominant AIRE mutations in mouse models reveals evidence for AIRE auto-regulation

Project description:Mechanistic dissection of dominant AIRE mutations in mouse models reveals evidence for AIRE auto-regulation

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Mechanistic dissection of dominant AIRE mutations in mouse models reveals evidence for AIRE auto-regulation [RNA-seq]

Project description:Mechanistic dissection of dominant AIRE mutations in mouse models reveals evidence for AIRE auto-regulation [RNA-seq]

| PRJNA634369 | ENA

Mechanistic dissection of dominant AIRE mutations in mouse models reveals evidence for AIRE auto-regulation [ATAC-seq]

Project description:Mechanistic dissection of dominant AIRE mutations in mouse models reveals evidence for AIRE auto-regulation [ATAC-seq]

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Mechanistic dissection of dominant AIRE mutations in mouse models reveals AIRE auto-regulation [ChIP-Seq]

Project description:Mechanistic dissection of dominant AIRE mutations in mouse models reveals AIRE auto-regulation [ChIP-Seq]

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Dominant-negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes.

Project description:Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive disease characterized by severe and childhood onset organ-specific autoimmunity caused by mutations in the autoimmune regulator (AIRE) gene. More recently, dominant-negative mutations within the PHD1, PHD2, and SAND domains have been associated with an incompletely penetrant milder phenotype with later onset familial clustering, often masquerading as organ-specific autoimmunity. Patients with immunodeficiencies or autoimmunity where genetic analyses revealed heterozygous AIRE mutations were included in the study and the dominant-negative effects of the AIRE mutations were functionally assessed in vitro. We here report additional families with phenotypes ranging from immunodeficiency, enteropathy, and vitiligo to asymptomatic carrier status. APS-1-specific autoantibodies can hint to the presence of these pathogenic AIRE variants although their absence does not rule out their presence. Our findings suggest functional studies of heterozygous AIRE variants and close follow-up of identified individuals and their families.

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