Importantly, PGE in the thymus, which is mediated by unique subset of epithelial cells called mTECs, triggers expression of vast majority of the genes from the whole genome (~85%).
[5] PGE was found to act in a stochastic manner, which means that each mTEC expresses distinct set of Aire-dependent and Aire-independent TRAs.
Moreover, Aire drives the PGE of Aire-dependent TRAs in B cells and because their repertoire is non-overlapping with that of mTECs it should broaden the scope of peripheral antigens displayed in the thymus.
There is available also alternative explanation, that Aire recognizes silenced chromatin thanks to interaction with molecular complex ATF7ip- MBD1 which binds methylated CpG di-nucleotides.
[29][30] Subsequently, Aire recruits elongation complex p-TEFb to the TSSs,[31] which releases stalled RNA II polymerases and therefore activates transcription (PGE) of Aire-dependent genes.
[30] Among these molecules further rank acetylase Creb-binding protein (CBP), which enhances stability of Aire, however dampens its transactivation properties and deacetylase Sirtuin 1 (Sirt1), which is essential for activation of PGE of Aire-dependent TRAs.
[34][35] Worth mentioning is also Hipk2, which phosphorylates Aire and CBP however, its absence affects mostly PGE of Aire-independent genes, suggesting that this kinase might cooperate with other unknown transcriptional regulator.
Nevertheless, several studies suggest that major role in triggering of Aire expression plays NF-κB signaling pathway,[38][39] similarly as in the development of mTECs.
[43] Even though little is known about its operation in the thymus, Fezf2, in marked contrast with Aire, plays role in different physiological processes than central tolerance, e.g. development of the brain, and acts as a classical transcription factor.
The repertoire of TRAs involved in Fezf2-driven PGE is nonoverlapping with that of Aire and comprises genes previously defined as Aire-independent, e.g. Fabp9 (TRA of testis).