The Mechanism of Tissue-Restricted Antigen Gene Expression by AIRE

Abstract

The autoimmune regulator is a critical transcription factor for generating central tolerance in the thymus. Recent studies have revealed how the autoimmune regulator targets many otherwise tissue-restricted Ag genes to enable negative selection of autoreactive T cells.

Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia

“…The recognition of H3K4me0 is unlikely to constitute the sole and essential mechanism by which AIRE and its binding partners target TRAs (Zumer et al 2013), not least because AIRE co-opts the repressive ATF7IP-MBD1 complex for the induction of immunotolerance (Waterfield et al 2014). Our findings suggest that the TSS of many genes regulated by Aire expression in mature mTEC is characterized by the presence of H3K27me3 together with absent or low levels of H3K4me3.…”

“…Presently, these remain largely unknown with the notable exception of the involvement of AIRE which interacts with proteins involved in chromatin structure, DNA damage response, gene transcription, and RNA processing (Abramson et al 2010;Gaetani et al 2012). Currently, AIRE is understood to act by recruiting the positive transcription elongation factor b (P-TEFb) to inactive genes at which stalled RNA polymerase II (Pol II) is already present (Zumer et al 2013). The functions of the various domains of AIRE have been the focus of several studies, with the second plant homeodomain (PHD2) and the C-terminal domain having been shown to be critical for the transactivation of target genes (Meloni et al 2008).…”

Homeodomain-Interacting Protein Kinase 2, a Novel Autoimmune Regulator Interaction Partner, Modulates Promiscuous Gene Expression in Medullary Thymic Epithelial Cells

“…The thymic transcriptional cofactor autoimmune regulator (Aire) is to date still the only identified molecular regulator specifically dedicated to control a sizeable fraction of the promiscuously expressed gene pool (7)(8)(9). It is currently thought that one major mode by which Aire targets such a wide array of genes is by relieving stalled polymerase II, thus allowing full-length transcription (10).…”

“…This mechanism would, at least in part, explain the significant enrichment of TRAs among the targets of Aire. In addition, Aire promotes induction of double-strand breaks and splicing of nascent mRNA transcripts (7)(8)(9)(10)12). Yet, there have to be other levels of Airedependent and -independent gene regulation, given the intricacies of pGE, that is, the mosaic expression pattern of TRAs at the population level and the TRA coexpression patterns at the single-cell level (13)(14)(15).…”

Autoimmune Disease in Primary Immunodeficiency

“…Promiscuous expression of tissue-restricted antigens (TRAs) by mTEC is regulated by a transcription factor called the autoimmune regulator, or AIRE. 3 The mechanism through which AIRE activates expression of TRAs is not fully elucidated, but requires oligomerization, nuclear localization, DNA binding, and interactions with other nuclear factors, 4 and mutations affecting these functions cause autoimmune polyendocrinopathy, candidiasis, and ectodermal dysplasia (APECED), also known as autoimmune polyendocrinopathy syndrome type 1 (APS-1), 5,6 a disease characterized by multiorgan autoimmunity with loss of tolerance to AIRE-regulated gene products. The most common organs involved are parathyroid and adrenal glands, b cells in the islets of Langerhans, and the liver.…”