Transcription factor playing an essential role to promote self-tolerance in the thymus by regulating the expression of a wide array of self-antigens that have the commonality of being tissue-restricted in their expression pattern in the periphery, called tissue restricted antigens (TRA) (Probable). Binds to G-doublets in an A/T-rich environment; the preferred motif is a tandem repeat of 5'-. ATTGGTTA-3' combined with a 5'-TTATTA-3' box. Binds to nucleosomes (By similarity). Binds to chromatin and interacts selectively with histone H3 that is not methylated at 'Lys-4', not phosphorylated at 'Thr-3' and not methylated at 'Arg-2'. Functions as a sensor of histone H3 modifications that are important for the epigenetic regulation of gene expression. Mainly expressed by medullary thymic epithelial cells (mTECs), induces the expression of thousands of tissue-restricted proteins, which are presented on major histocompatibility complex class I (MHC-I) and MHC-II molecules to developing T-cells percolating through the thymic medulla (By similarity). Also induces self-tolerance through other mechanisms such as the regulation of the mTEC differentiation program (PubMed:19015306). Controls the medullary accumulation of thymic dendritic cells and the development of regulatory T-cell through the regulation of XCL1 expression (PubMed:21300913). Regulates the production of CCR4 and CCR7 ligands in medullary thymic epithelial cells and alters the coordinated maturation and migration of thymocytes (PubMed:19923453). In thimic B-cells, allows the presentation of licensing-dependent endogenous self-anitgen for negative selection (PubMed:26070482). In secondary lymphoid organs, induces functional inactivation of CD4(+) T-cells. Expressed by a distinct bone marrow-derived population, induces self-tolerance through a mechanism that does not require regulatory T-cells and is resitant to innate inflammatory stimuli (PubMed:23993652). Homodimer and homotetramer. Interacts with CREBBP. Interacts preferentially with histone H3 that is not methylated at 'Lys-4'. Binds with lower affinity to histone H3 that is monomethylated at 'Lys-4'. Trimethylation of histone H3 at 'Lys-4' or phosphorylation at 'Thr-3' abolish the interaction. Binds with lower affinity to histone H3 that is acetylated at 'Lys-4', or that is acetylated at 'Lys-9' or trimethylated at 'Lys-9'. Binds histone H3 that is dimethylated at 'Arg-2' with very low affinity (By similarity). Predominantly nuclear but also cytoplasmic. Found in nuclear body-like structures (dots) and in a filamentous vimentin-like pattern. Additional isoforms seem to exist. Highly expressed in a few cells in the medulla of the thymus (medullary epithelial cells) (at protein level) (PubMed:23993652). Expressed in thymic but no peripheral B-cells (PubMed:26070482). In secondary lymphoid organs, expressed in a discrete population of bone marrow-derived toleregenic antigen presenting cells (APCs) called extrathymic AIRE expressing cells (eTAC)(at protein level) (PubMed:23993652). Detected at very low levels in thymus, lymph node, liver, brain, ovary, lung, testis, kidney, heart, spleen, bone marrow, skeletal muscle and adrenal gland. Isoforms 1a to 1d predominate, isoforms 2a to 2d are intermediate and isoforms 3a to 3d are expressed at extremely low levels. In the thymus, not expressed at 13.5 dpc but present at 16.5 dpc and postnatal day 1. Interacts via the first PHD domain with the N-terminus of histone H3 that is not methylated at 'Lys-4'. Disruption of the first PHD domain has been shown to lead to reduced transcriptional activity and to localization of the protein mainly in the cytoplasm in small granules. While the PHD zinc fingers are necessary for the transactivation capacity of the protein, other regions also modulate this function (By similarity). The L-X-X-L-L repeats may be implicated in binding to nuclear receptors. The N-terminal HSR domain is required for localization on tubular structures. Phosphorylated. Deficient mice show an altered thymic organization with altered morphology and location of mTECs (PubMed:19015306). They exhibit defective accumulation of thymic dendritic cells in the medullary region and generation of naturally ocurring T cells in the thymus (PubMed:21300913). Probably inactive. Probably inactive. Probably inactive. Probably inactive.