The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression

Abstract

Mutations in the gene autoimmune regulator (AIRE) cause autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. AIRE is expressed in thymic medullary epithelial cells, where it promotes the expression of tissue-restricted antigens. By the combined use of biochemical and biophysical methods, we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger (AIRE-PHD1) and preferentially binds to non-methylated H3K4 (H3K4me0). Accordingly, in vivo AIRE binds to and activates promoters containing low levels of H3K4me3 in human embryonic kidney 293 cells. We conclude that AIRE-PHD1 is an important member of a newly identified class of PHD fingers that specifically recognize H3K4me0, thus providing a new link between the status of histone modifications and the regulation of tissue-restricted antigen expression in thymus.

Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases

“…This probably reflects the different and unique roles of the individual domains of the AIRE protein. Specifically, whereas the CARD domain is shown to be critical for AIRE homo-oligomerization and speckled nuclear localization (Bjö rses et al, 1999;Kumar et al, 2001), the PHD domain of AIRE functions as an epigenetic reader, specifically recognizing unmethylated lysine 4 on histone 3 (H3K4me0) (Org et al, 2008). The PHD1 domain is shown to be absolutely critical for AIRE's transcription-transactivation activity, as well as for its capacity to prevent multiorgan autoimmunity in transgenic mouse models Koh et al, 2008Koh et al, , 2010.…”

“…Indeed, a substitution of the cysteine with tyrosine predicts disruption of PHD1 folding ( Figure 3B; Chakravarty et al, 2009). Additional structural analyses revealed that many of the reported missense mutations changed amino acids that were conserved among different species (Figures 3B and S5;Bjö rses et al, 2000;Org et al, 2008;Spiliotopoulos et al, 2012) and could similarly affect the Zn 2+ -binding or folding of the domain.…”

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy

“…Both AIRE PHD fingers constitute a structural platform for the direct or indirect recruitment of other chromatin-related proteins and are involved in AIRE transcriptional activity [47,48]. Additionally, the first PHD domain functions as a histone code reader that interacts with unmethylated histone H3 lysine residue 4 that is characteristic of inactive chromatin or genes with no or very low transcriptional activity [49][50][51]. AIRE interacts with and coactivates transcriptional regulator CBP [52] and recruits other factors, such as positive elongation factor b (P-TEFb), to phosphorylate the stalled RNA polymerase II (RNAPII), resulting in its reactivation and transcriptional elongation of the target genes [53][54][55].…”

Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance

“…Rather than acting as a classical DNA sequence-specific transcription factor, Aire might 'identify' its targets through binding epigenetic chromatin modifications associated with inactive gene loci [4]. Subsequently, this might allow for the recruitment of molecular machineries that facilitate 'illegitimate' transcription by generating double-strand breaks in the underlying DNA and at the same time afford robustness to low levels of transcription by fostering mRNA processing [5].…”