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2030-01-01
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- IOC - Artigos de Periódicos [12973]
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EVIDENCE FOR A NETWORK TRANSCRIPTIONAL CONTROL OF PROMISCUOUS GENE EXPRESSION IN MEDULLARY THYMIC EPITHELIAL CELLS
Redes Reguladoras de Genes
Autoimunidade
Autoantígeno
Expressão Gênica
Células epiteliais do timo medular
Expressão gênica promíscua
Tolerância central da célula T
Medullary thymic epithelial cells
Promiscuous gene expression
Aire
Gene network
Central T cell tolerance
Autoantigen
Autoimmunity
Author
Affilliation
Abstract
The expression of peripheral tissue antigens (PTAs) in the thymus by medullary thymic epithelial cells
(mTECs) is essential for the central self-tolerance in the generation of the T cell repertoire. Due to heterogeneity
of autoantigen representation, this phenomenon has been termed promiscuous gene expression
(PGE), in which the autoimmune regulator (Aire) gene plays a key role as a transcription factor in part
of these genes. Here we used a microarray strategy to access PGE in cultured murine CD80+ 3.10 mTEC
line. Hierarchical clustering of the data allowed observation that PTA genes were differentially expressed
being possible to found their respective induced or repressed mRNAs. To further investigate the control
of PGE, we tested the hypothesis that genes involved in this phenomenon might also be modulated
by transcriptional network. We then reconstructed such network based on the microarray expression
data, featuring the guanylate cyclase 2d (Gucy2d) gene as a main node. In such condition, we established
167 positive and negative interactions with downstream PTA genes. Silencing Aire by RNA interference,
Gucy2d while down regulated established a larger number (355) of interactions with PTA genes. T- and
G-boxes corresponding to AIRE protein binding sites located upstream to ATG codon of Gucy2d supports
this effect. These findings provide evidence that Aire plays a role in association with Gucy2d, which is
connected to several PTA genes and establishes a cascade-like transcriptional control of promiscuous
gene expression in mTEC cells.
Keywords in Portuguese
TimoRedes Reguladoras de Genes
Autoimunidade
Autoantígeno
Expressão Gênica
Células epiteliais do timo medular
Expressão gênica promíscua
Tolerância central da célula T
Keywords
ThymusMedullary thymic epithelial cells
Promiscuous gene expression
Aire
Gene network
Central T cell tolerance
Autoantigen
Autoimmunity
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