Aire’s plant homeodomain(PHD)-2 is critical for induction of immunological tolerance

Abstract

Aire impacts immunological tolerance by regulating the expression of a large set of genes in thymic medullary epithelial cells, thereby controlling the repertoire of self-antigens encountered by differentiating thymocytes. Both humans and mice lacking Aire develop multiorgan autoimmunity. Currently, there are few molecular details on how Aire performs this crucial function. The more amino-terminal of its two plant homeodomains (PHDs), PHD1, helps Aire target poorly transcribed loci by "reading" the methylation status of a particular lysine residue of histone-3, a process that does not depend on the more carboxyl-terminal PHD-2. This study addresses the role of PHD2 in Aire function by comparing the behavior of wild-type and PHD2-deleted Aire in both transfected cells and transgenic mice. PHD2 was required for Aire to interact with sets of protein partners involved in chromatin structure/binding or transcription but not with those implicated in pre-mRNA processing; it also was not required for Aire's nuclear translocation or regional distribution. PHD2 strongly influenced the ability of Aire to regulate the medullary epithelial cell transcriptome and so was crucial for effective central tolerance induction. Thus, Aire's two PHDs seem to play distinct roles in the scenario by which it assures immunological tolerance.negative selection | protein-protein interactions | thymus | transcription factor

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

“…AIRE has been shown to interact with ChromodomainHelicase-DNA (CHD) members 4 and 6 (Gaetani et al 2012;Yang et al 2013). CHD4 binds to unmethylated H3K4 and trimethylated H3K9 (Musselman et al 2009;Mansfield et al 2011), whereas CHD6 is known to interact with H3K27me3 (Alfonso et al 2011).…”

AIRE expands: new roles in immune tolerance and beyond

“…For instance, interacting proteins have been described that help Aire to recognize and target TSA genes 25–30 , release stalled RNA polymerase to allow RNA elongation 24, 31–33 , and regulate Aire itself 34–38 . Additionally, inroads have been made into mapping the regions of Aire that bind to interacting partners 25, 38, 39 (Figure 3B). These recent developments in understanding how Aire functions at a molecular level are described in detail below.…”

Immune Dysregulation Leading to Chronic Autoimmunity

“…8,9 The PHD2 finger aids in this process by binding to protein partners involved in chromatin structure/binding or transcription. 10 Once bound to inactive chromatin, AIRE helps initiate the transcription of silenced genes found therein, by several mechanisms. These include promoting the formation of transcription initiation complexes, and rescuing sterile initiation complexes that are unable to proceed due to a paused RNA polymerase-II by recruiting the positive tissue elongation factor (P-TEFb).…”