Shown are two of the major known Aire-expressing cell populations in the thymus (mTEC) and the periphery (eTAC). Recent work has demonstrated that AIRE promotes the transcription of an array of a complementary set of genes in the two cell populations. The number of Aire-induced genes in the periphery also appears to be smaller and may reflect a lower level of Aire expression within this cell population. As outlined in the text, AIRE has been shown to bind to and interact with a number of proteins that are involved in transcription, including CBP, P-TEFb, and DNA-PK. AIRE localizes intracellulary in mTEC’s to nuclear speckles which are enriched for a variety of splicing factors that may also participate in its regulation of transcription. The PHD1 domain of AIRE has been shown to have specificity for the H3K4me0 mark on chromatin suggesting a mechanism by which AIRE may target repressed or inactive genes. Taken together, a picture is emerging in which AIRE may promote transcription through epigenetic mechanisms and a collaboration with a variety of co-factors. The exact identity and contribution of these interactions to the regulation of AIRE-dependent transcription in eTAC’s and mTEC’s remains to be determined.