Transcriptional regulation by AIRE: molecular mechanisms of central tolerance

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Abstract
Autoimmune regulator (AIRE) protein is mainly expressed by mature medullary thymic epithelial cells, in which it promotes the promiscuous expression of many tissue-specific antigens (TSAs). TSAs that are upregulated by AIRE are presented to developing thymocytes, and this is required for efficient negative selection. Aberrant negative selection in the absence of AIRE leads to the escape of self-reactive thymocytes to the periphery and subsequent autoimmunity. AIRE contains several domains that are characteristic of transcriptional regulators and chromatin-binding proteins, such as a caspase-recruitment domain (CARD), a SP100, AIRE1, NucP41/P75 and DEAF1 (SAND) domain and plant homeodomain (PHD) zinc fingers. Concordantly, many studies have confirmed that AIRE is as a potent transcriptional activator. Several proteins have been found to interact with AIRE, including CREB-binding protein (CBP), protein inhibitor of activated STAT1 (PIAS1), DNA-dependent protein kinase (DNA-PK), histone H3 unmethylated at lysine 4 and the positive transcription elongation factor b (P-TEFb). Interaction with histone H3 that is unmethylated at lysine 4 allows AIRE to bind to certain chromatin regions. At target gene promoters, AIRE promotes transcriptional elongation by binding and recruiting the P-TEFb complex to RNA polymerase II. AIRE-regulated genes tend to cluster in the genome; however, recent findings indicate that at a single-cell level, the expression of TSAs varies, which suggests that gene activation by AIRE can be a stochastic event.