O papel modulador do gene AIRE - capes

Promiscuous gene expression in medullary thymic epithelial cells isconnected in network where the Aire gene is an upstream modulatorABSTRACTThe expression of tissue restricted antigens (TRAs) in thymus bymedullary thymic epithelial cells (mTECs) is essential for the central selftoleranceof T cells.Due to heterogeneity of autoantigen representation this phenomenon hasbeen termed promiscuous gene expression (PGE), in which the autoimmuneregulator (Aire) gene plays a role as main positive transcriptional regulator on alarge set of Aire-dependent TRAs.Aire protein is able in binding to specific DNA sequence motifs andplays a role as a direct regulator.Here we used the cDNA microarray method to access PGE in murineCD80 + mTECs cultured in vitro. Hierarchical clustering of the data allowedobservation that TRA genes were differentially expressed. To furtherinvestigate the control of PGE, we hypothesize that TRA genes establishnetworks contributing it selves to modulate their transcriptional levels. Aire inthis case plays a role as upstream positive modulator. To test this hypothesis,initially we silenced Aire by gene knockdown (RNA interference) in mTECs.Hierarchical clustering of cDNA microarray data showed a set of AiredependentTRAs genes, which were down regulated after Aire silencing. Genenetworks reconstructed from these data allowed the identification of a genenode (Gucy2d) establishing positive regulation upon downstream genes innormal mTECs. Nevertheless, under silencing of Aire, Gucy2d has become arepressor.These finding evidentiate that, genes features in PGE are connected innetwork; a gene node may act as intermediate in their control and that Aire inPGE network plays a role as an upstream regulator.ii