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.
Summary Endothelium in embryonic hematopoietic tissues generates hematopoietic stem/progenitor cells; however, it is unknown how its unique potential is specified. We show that transcription factor Scl/Tal1 is essential for both establishing the hematopoietic transcriptional program in hemogenic endothelium and preventing its misspecification to a cardiomyogenic fate. Scl−/− embryos activated a cardiac transcriptional program in yolk sac endothelium, leading to the emergence of CD31+Pdgfrα+ cardiogenic precursors that generated spontaneously beating cardiomyocytes. Ectopic cardiogenesis was also observed in Scl−/− hearts, where the disorganized endocardium precociously differentiated into cardiomyocytes. Induction of mosaic deletion of Scl in Sclfl/fl Rosa26Cre-ERT2 embryos revealed a cell-intrinsic, temporal requirement for Scl to prevent cardiomyogenesis from endothelium. Scl−/− endothelium also upregulated the expression of Wnt antagonists, which promoted rapid cardiomyocyte differentiation of ectopic cardiogenic cells. These results reveal unexpected plasticity in embryonic endothelium such that loss of a single master regulator can induce ectopic cardiomyogenesis from endothelial cells.
The negative selection of T cells in the thymus is necessary for the maintenance of self tolerance. Thymic medullary epithelial cells have a key function in this process as they express a large number of tissue-specific self antigens that are presented to developing T cells. Mutations in the transcriptional regulator AIRE cause a breakdown of central tolerance associated with decreased expression of self antigens in the thymus. In this Review, we discuss the role of AIRE in the thymus and recent advances in our understanding of how AIRE might function to regulate gene expression.Autoimmunity is caused by the breakdown of mechanisms that maintain immune tolerance to self tissues. Most self-reactive T cells are deleted in the thymus, resulting in central tolerance [G], which is further supported by regulatory mechanisms outside of primary lymphoid tissues, which are collectively known as peripheral tolerance. As the main mechanism of central tolerance, the negative selection [G] of self-reactive thymocytes occurs mainly in the medullary compartment of the thymus 1, 2. The medullary thymic epithelial cells (mTECs) express a large number of genes, including tissue-specific antigens (TSAs, also named tissue-restricted antigens or peripheral tissue antigens) that are normally present only in specialized peripheral organs and are apparently not required for the direct function of mTECs 3, 4. During negative selection, these encoded TSAs are presented by mTECs or dendritic cells to differentiating thymocytes as self antigens5, 6, leading to the Correspondence: Pärt Peterson, PhD, Molecular Pathology, Ravila 19, Biomedicum, University of Tartu, Tartu 50411, Estonia, Phone: +372 7374202, Fax: +372 7374207, part.peterson@ut.ee. Online at-a-glance summary • AIRE is mainly expressed by mature thymic medullary epithelial cells, where it promotes the promiscuous expression of many tissue-specific antigens (TSAs).• TSAs that are upregulated by AIRE are presented to developing thymocytes, and this is required for efficient negative selection. Aberrant negative selection in the absence of AIRE leads to the escape of self-reactive thymocytes to the periphery and subsequent autoimmunity.• AIRE contains several domains that are characteristic of transcriptional regulators and chromatin-binding proteins, such as a CARD, a SAND domain and PHD fingers. Concordantly, many studies have confirmed AIRE's function as a potent transcriptional activator.• Several proteins have been found to interact with AIRE, including CBP, PIAS1, DNA-PK, histone H3 with an unmethylated N-terminus (lysine 4) and P-TEFb.• Interaction with histone H3 that is unmethylated at lysine 4 allows AIRE to bind to certain chromatin regions. At target gene promoters, AIRE promotes transcriptional elongation by binding and recruiting the positive transcription elongation factor b (P-TEFb) complex to RNA polymerase II.• AIRE-regulated genes tend to cluster in the genome; however, recent findings indicate that at a single-cell level, the expression of TSAs varies, ...
Background and Purpose-Recent evidence has implicated the genes for 5-lipoxygenase activating protein (ALOX5AP) and phosphodiesterase 4D (PDE4D) as susceptibility genes for stroke in the Icelandic population. The aim of the present study was to explore the role of these genes in a central European population of stroke patients. Methods-A total of 639 consecutive stroke patients and 736 unrelated population-based controls that had been matched for age and sex were examined using a case-control design. Twenty-two single-nucleotide polymorphisms (SNPs) covering ALOX5AP were genotyped. For PDE4D, microsatellite AC008818-1 and 12 SNPs, which tag all common haplotypes in previously identified linkage disequilibrium (LD) blocks, were analyzed. Results-A nominally significant association with stroke was observed with several SNPs from ALOX5AP, including SNP SG13S114, which had been part of the Icelandic at-risk haplotype. Associations were stronger in males than in females, with SG13S114 (odds ratio,
Plant homeodomain (PHD) fingers are often present in chromatin-binding proteins and have been shown to bind histone H3 N-terminal tails. Mutations in the autoimmune regulator (AIRE) protein, which harbours two PHD fingers, cause a rare monogenic disease, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE activates the expression of tissue-specific antigens by directly binding through its first PHD finger (AIRE-PHD1) to histone H3 tails non-methylated at K4 (H3K4me0). Here, we present the solution structure of AIRE-PHD1 in complex with H3K4me0 peptide and show that AIRE-PHD1 is a highly specialized non-modified histone H3 tail reader, as post-translational modifications of the first 10 histone H3 residues reduce binding affinity. In particular, H3R2 dimethylation abrogates AIRE-PHD1 binding in vitro and reduces the in vivo activation of AIRE target genes in HEK293 cells. The observed antagonism by R2 methylation on AIRE-PHD1 binding is unique among the H3K4me0 histone readers and represents the first case of epigenetic negative cross-talk between non-methylated H3K4 and methylated H3R2. Collectively, our results point to a very specific histone code responsible for non-modified H3 tail recognition by AIRE-PHD1 and describe at atomic level one crucial step in the molecular mechanism responsible for antigen expression in the thymus.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.