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

Abstract

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation or the creation of derivative works without specific permission.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.

Aire employs a histone-binding module to mediate immunological tolerance, linking chromatin regulation with organ-specific autoimmunity

“…The family of PHD fingers recognizing the unmodified N terminus of H3 includes BHC80 and DNMT3L, and potentially extends to Sp110 and Sp140, which share key recognition residues (34). Histone PTM readers interacting with the unmodified amino termini of H3 and H4 tails have been associated with hypoacetylation and transcriptional silencing (39), which is consistent with BHC80's role as a subunit of the lysine demethylase-1 corepressor complex associated with transcriptional repression of neuron-specific genes (40).…”

Ovarian autoimmune disease: clinical concepts and animal models

“…[78][79][80] These PHD domains associate with histone 3 at unmethylated lysine 4 residues (H3K4me0), which are typically within transcriptionally inactive chromatin regions, and in combination with DNA-dependent protein kinase, appear to promote subsequent transcription. [81][82][83] Consistent with this model of transcriptional regulation, AIREregulated genes are chromosomally clustered and stochastically expressed. 68,[84][85][86] Additionally, immunochemical localization suggests that AIRE associates with the nuclear matrix in a distinctive speckling pattern (Figure 2).…”

Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

“…However, our data point to a critical interaction between acetylated lysine residues in the CARD of Aire and the amino-terminal bromodomain, BD1, of Brd4. A higher-level, perhaps dynamic (22), tripartite interaction among Brd4, Aire, and acetylated histones remains possible, given that Aire's PHD1 binds to the eight amino-terminal residues of unmodified histone H3 (26,43). Indeed, such a structure might explain the strong dependence of the Aire:Brd4 interaction on Aire's PHD1 (Fig.…”