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Part Peterson - One of the best experts on this subject based on the ideXlab platform.
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dna breaks and chromatin structural changes enhance the transcription of Autoimmune Regulator target genes
Journal of Biological Chemistry, 2017Co-Authors: Mithu Guha, Mario Saare, Kai Kisand, Ingrid Liiv, Julia Maslovskaja, Uku Haljasorg, Tonis Tasa, Andres Metspalu, Lili Milani, Part PetersonAbstract:Abstract The Autoimmune Regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T-cells by promoting the ectopic expression of tissue-specific genes in thymic medullary epithelium. Mutations in AIRE cause a monogenic Autoimmune disease called Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA-seq, we found that the inhibition of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes with low expression levels. AIRE-mediated transcription was not only enhanced by TOP2 inhibition but also by topoisomerase 1 (TOP1) inhibitor camptothecin. The transcriptional activation was associated with structural rearrangements in chromatin, notably the accumulation of γH2AX and the exchange of histone H1 with HMGB1 at AIRE target gene promoters. In addition, we found the transcriptional upregulation to co-occur with the chromatin structural changes within the genomic cluster of carcino-embryonic antigen-like cellular adhesion molecule (CEACAM) genes. Overall, our results suggest that the presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes.
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DNA breaks and chromatin structural changes enhance the transcription of Autoimmune Regulator target genes
The Journal of biological chemistry, 2017Co-Authors: Mithu Guha, Mario Saare, Kai Kisand, Ingrid Liiv, Julia Maslovskaja, Uku Haljasorg, Tonis Tasa, Andres Metspalu, Lili Milani, Part PetersonAbstract:The Autoimmune Regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T cells by promoting the ectopic expression of tissue-specific genes in the thymic medullary epithelium. Mutations in AIRE cause a monogenic Autoimmune disease called Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA sequencing, we found that inhibition of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes with low expression levels. AIRE-mediated transcription was not only enhanced by TOP2 inhibition but also by the TOP1 inhibitor camptothecin. The transcriptional activation was associated with structural rearrangements in chromatin, notably the accumulation of γH2AX and the exchange of histone H1 with HMGB1 at AIRE target gene promoters. In addition, we found the transcriptional up-regulation to co-occur with the chromatin structural changes within the genomic cluster of carcinoembryonic antigen-like cellular adhesion molecule genes. Overall, our results suggest that the presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes.
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Autoimmune Regulator is acetylated by transcription coactivator cbp p300
Experimental Cell Research, 2012Co-Authors: Mario Saare, Ana Rebane, Balaji Rajashekar, Jaak Vilo, Part PetersonAbstract:The Autoimmune Regulator (AIRE) is a Regulator of transcription in the thymic medulla, where it controls the expression of a large set of peripheral-tissue specific genes. AIRE interacts with the transcriptional coactivator and acetyltransferase CBP and synergistically cooperates with it in transcriptional activation. Here, we aimed to study a possible role of AIRE acetylation in the modulation of its activity. We found that AIRE is acetylated in tissue culture cells and this acetylation is enhanced by overexpression of CBP and the CBP paralog p300. The acetylated lysines were located within nuclear localization signal and SAND domain. AIRE with mutations that mimicked acetylated K243 and K253 in the SAND domain had reduced transactivation activity and accumulated into fewer and larger nuclear bodies, whereas mutations that mimicked the unacetylated lysines were functionally similar to wild-type AIRE. Analogously to CBP, p300 localized to AIRE-containing nuclear bodies, however, the overexpression of p300 did not enhance the transcriptional activation of AIRE-regulated genes. Further studies showed that overexpression of p300 stabilized the AIRE protein. Interestingly, gene expression profiling revealed that AIRE, with mutations mimicking K243/K253 acetylation in SAND, was able to activate gene expression, although the affected genes were different and the activation level was lower from those regulated by wild-type AIRE. Our results suggest that the AIRE acetylation can influence the selection of AIRE activated genes.
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Autoimmune Regulator is acetylated by transcription coactivator CBP/p300
Experimental cell research, 2012Co-Authors: Mario Saare, Ana Rebane, Balaji Rajashekar, Jaak Vilo, Part PetersonAbstract:The Autoimmune Regulator (AIRE) is a Regulator of transcription in the thymic medulla, where it controls the expression of a large set of peripheral-tissue specific genes. AIRE interacts with the transcriptional coactivator and acetyltransferase CBP and synergistically cooperates with it in transcriptional activation. Here, we aimed to study a possible role of AIRE acetylation in the modulation of its activity. We found that AIRE is acetylated in tissue culture cells and this acetylation is enhanced by overexpression of CBP and the CBP paralog p300. The acetylated lysines were located within nuclear localization signal and SAND domain. AIRE with mutations that mimicked acetylated K243 and K253 in the SAND domain had reduced transactivation activity and accumulated into fewer and larger nuclear bodies, whereas mutations that mimicked the unacetylated lysines were functionally similar to wild-type AIRE. Analogously to CBP, p300 localized to AIRE-containing nuclear bodies, however, the overexpression of p300 did not enhance the transcriptional activation of AIRE-regulated genes. Further studies showed that overexpression of p300 stabilized the AIRE protein. Interestingly, gene expression profiling revealed that AIRE, with mutations mimicking K243/K253 acetylation in SAND, was able to activate gene expression, although the affected genes were different and the activation level was lower from those regulated by wild-type AIRE. Our results suggest that the AIRE acetylation can influence the selection of AIRE activated genes.
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Increased apoptosis after Autoimmune Regulator expression in epithelial cells revealed by a combined quantitative proteomics approach.
Journal of proteome research, 2010Co-Authors: Núria Colomé, Part Peterson, Ingrid Liiv, Javier Collado, Joan Josep Bech-serra, Luis C. Antón, Francesc Canals, Dolores Jaraquemada, Iñaki AlvarezAbstract:Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive Autoimmune disease, affecting many endocrine tissues. APECED is associated to the lack of function of a single gene called Autoimmune Regulator (AIRE). Aire knockout mice develop various Autoimmune disorders affecting different organs, indicating that Aire is a key gene in the control of organ-specific Autoimmune diseases. AIRE is mainly expressed by medullary thymic epithelial cells (mTECs), and its absence results in the loss of tolerance against tissue restricted antigens (TRAs). Aire induces the transcription of genes encoding for TRAs in mTECs. In this report, the analysis of AIRE’s effect on the cellular proteome was approached by the combination of two quantitative proteomics techniques, 2D-DIGE and ICPL, using an AIRE-transfected and nontransfected epithelial cell line. The results showed increased levels of several chaperones, (HSC70, HSP27 and tubulin-specific chaperone A) in AIRE-expressing cel...
Mario Saare - One of the best experts on this subject based on the ideXlab platform.
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dna breaks and chromatin structural changes enhance the transcription of Autoimmune Regulator target genes
Journal of Biological Chemistry, 2017Co-Authors: Mithu Guha, Mario Saare, Kai Kisand, Ingrid Liiv, Julia Maslovskaja, Uku Haljasorg, Tonis Tasa, Andres Metspalu, Lili Milani, Part PetersonAbstract:Abstract The Autoimmune Regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T-cells by promoting the ectopic expression of tissue-specific genes in thymic medullary epithelium. Mutations in AIRE cause a monogenic Autoimmune disease called Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA-seq, we found that the inhibition of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes with low expression levels. AIRE-mediated transcription was not only enhanced by TOP2 inhibition but also by topoisomerase 1 (TOP1) inhibitor camptothecin. The transcriptional activation was associated with structural rearrangements in chromatin, notably the accumulation of γH2AX and the exchange of histone H1 with HMGB1 at AIRE target gene promoters. In addition, we found the transcriptional upregulation to co-occur with the chromatin structural changes within the genomic cluster of carcino-embryonic antigen-like cellular adhesion molecule (CEACAM) genes. Overall, our results suggest that the presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes.
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DNA breaks and chromatin structural changes enhance the transcription of Autoimmune Regulator target genes
The Journal of biological chemistry, 2017Co-Authors: Mithu Guha, Mario Saare, Kai Kisand, Ingrid Liiv, Julia Maslovskaja, Uku Haljasorg, Tonis Tasa, Andres Metspalu, Lili Milani, Part PetersonAbstract:The Autoimmune Regulator (AIRE) protein is the key factor in thymic negative selection of autoreactive T cells by promoting the ectopic expression of tissue-specific genes in the thymic medullary epithelium. Mutations in AIRE cause a monogenic Autoimmune disease called Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. AIRE has been shown to promote DNA breaks via its interaction with topoisomerase 2 (TOP2). In this study, we investigated topoisomerase-induced DNA breaks and chromatin structural alterations in conjunction with AIRE-dependent gene expression. Using RNA sequencing, we found that inhibition of TOP2 religation activity by etoposide in AIRE-expressing cells had a synergistic effect on genes with low expression levels. AIRE-mediated transcription was not only enhanced by TOP2 inhibition but also by the TOP1 inhibitor camptothecin. The transcriptional activation was associated with structural rearrangements in chromatin, notably the accumulation of γH2AX and the exchange of histone H1 with HMGB1 at AIRE target gene promoters. In addition, we found the transcriptional up-regulation to co-occur with the chromatin structural changes within the genomic cluster of carcinoembryonic antigen-like cellular adhesion molecule genes. Overall, our results suggest that the presence of AIRE can trigger molecular events leading to an altered chromatin landscape and the enhanced transcription of low-expressed genes.
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Autoimmune Regulator is acetylated by transcription coactivator cbp p300
Experimental Cell Research, 2012Co-Authors: Mario Saare, Ana Rebane, Balaji Rajashekar, Jaak Vilo, Part PetersonAbstract:The Autoimmune Regulator (AIRE) is a Regulator of transcription in the thymic medulla, where it controls the expression of a large set of peripheral-tissue specific genes. AIRE interacts with the transcriptional coactivator and acetyltransferase CBP and synergistically cooperates with it in transcriptional activation. Here, we aimed to study a possible role of AIRE acetylation in the modulation of its activity. We found that AIRE is acetylated in tissue culture cells and this acetylation is enhanced by overexpression of CBP and the CBP paralog p300. The acetylated lysines were located within nuclear localization signal and SAND domain. AIRE with mutations that mimicked acetylated K243 and K253 in the SAND domain had reduced transactivation activity and accumulated into fewer and larger nuclear bodies, whereas mutations that mimicked the unacetylated lysines were functionally similar to wild-type AIRE. Analogously to CBP, p300 localized to AIRE-containing nuclear bodies, however, the overexpression of p300 did not enhance the transcriptional activation of AIRE-regulated genes. Further studies showed that overexpression of p300 stabilized the AIRE protein. Interestingly, gene expression profiling revealed that AIRE, with mutations mimicking K243/K253 acetylation in SAND, was able to activate gene expression, although the affected genes were different and the activation level was lower from those regulated by wild-type AIRE. Our results suggest that the AIRE acetylation can influence the selection of AIRE activated genes.
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Autoimmune Regulator is acetylated by transcription coactivator CBP/p300
Experimental cell research, 2012Co-Authors: Mario Saare, Ana Rebane, Balaji Rajashekar, Jaak Vilo, Part PetersonAbstract:The Autoimmune Regulator (AIRE) is a Regulator of transcription in the thymic medulla, where it controls the expression of a large set of peripheral-tissue specific genes. AIRE interacts with the transcriptional coactivator and acetyltransferase CBP and synergistically cooperates with it in transcriptional activation. Here, we aimed to study a possible role of AIRE acetylation in the modulation of its activity. We found that AIRE is acetylated in tissue culture cells and this acetylation is enhanced by overexpression of CBP and the CBP paralog p300. The acetylated lysines were located within nuclear localization signal and SAND domain. AIRE with mutations that mimicked acetylated K243 and K253 in the SAND domain had reduced transactivation activity and accumulated into fewer and larger nuclear bodies, whereas mutations that mimicked the unacetylated lysines were functionally similar to wild-type AIRE. Analogously to CBP, p300 localized to AIRE-containing nuclear bodies, however, the overexpression of p300 did not enhance the transcriptional activation of AIRE-regulated genes. Further studies showed that overexpression of p300 stabilized the AIRE protein. Interestingly, gene expression profiling revealed that AIRE, with mutations mimicking K243/K253 acetylation in SAND, was able to activate gene expression, although the affected genes were different and the activation level was lower from those regulated by wild-type AIRE. Our results suggest that the AIRE acetylation can influence the selection of AIRE activated genes.
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Cooperative activation of transcription by Autoimmune Regulator AIRE and CBP.
Biochemical and biophysical research communications, 2005Co-Authors: Jukka Pitkanen, Ana Rebane, J. Rowell, Astrid Murumägi, Philipp Ströbel, Kaidi Möll, Mario Saare, J. Heikkilä, V. Doucas, Alexander MarxAbstract:Abstract Autoimmune Regulator (AIRE) is a transcriptional Regulator that is believed to control the expression of tissue-specific genes in the thymus. Mutated AIRE is responsible for onset of the hereditary Autoimmune disease APECED. AIRE is able to form nuclear bodies (NBs) and interacts with the ubiquitous transcriptional coactivator CBP. In this paper, we show that CBP and AIRE synergistically activate transcription on different promoter reporters whereas AIRE gene mutation R257X, found in APECED patients, interferes with this coactivation effect. Furthermore, the overexpression of AIRE and CBP collaboratively enhance endogenous IFNβ mRNA expression. The immunohistochemical studies suggest that CBP, depending on the balance of nuclear proteins, is a component of AIRE NBs. We also show that AIRE NBs are devoid of active chromatin and, therefore, not sites of transcription. In addition, we demonstrate by 3D analyses that AIRE and CBP, when colocalizing, are located spatially differently within AIRE NBs. In conclusion, our data suggest that AIRE activates transcription of the target genes, i.e., autoantigens in collaboration with CBP and that this activation occurs outside of AIRE NBs.
Jukka Pitkanen - One of the best experts on this subject based on the ideXlab platform.
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Cooperative activation of transcription by Autoimmune Regulator AIRE and CBP.
Biochemical and biophysical research communications, 2005Co-Authors: Jukka Pitkanen, Ana Rebane, J. Rowell, Astrid Murumägi, Philipp Ströbel, Kaidi Möll, Mario Saare, J. Heikkilä, V. Doucas, Alexander MarxAbstract:Abstract Autoimmune Regulator (AIRE) is a transcriptional Regulator that is believed to control the expression of tissue-specific genes in the thymus. Mutated AIRE is responsible for onset of the hereditary Autoimmune disease APECED. AIRE is able to form nuclear bodies (NBs) and interacts with the ubiquitous transcriptional coactivator CBP. In this paper, we show that CBP and AIRE synergistically activate transcription on different promoter reporters whereas AIRE gene mutation R257X, found in APECED patients, interferes with this coactivation effect. Furthermore, the overexpression of AIRE and CBP collaboratively enhance endogenous IFNβ mRNA expression. The immunohistochemical studies suggest that CBP, depending on the balance of nuclear proteins, is a component of AIRE NBs. We also show that AIRE NBs are devoid of active chromatin and, therefore, not sites of transcription. In addition, we demonstrate by 3D analyses that AIRE and CBP, when colocalizing, are located spatially differently within AIRE NBs. In conclusion, our data suggest that AIRE activates transcription of the target genes, i.e., autoantigens in collaboration with CBP and that this activation occurs outside of AIRE NBs.
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Subcellular expression of Autoimmune Regulator is organized in a spatiotemporal manner
The Journal of biological chemistry, 2004Co-Authors: Hiroko Akiyoshi, Jukka Pitkanen, Vassilis Doucas, Jun Kudoh, Shigetsugu Hatakeyama, Yasuhiro Mouri, Kyoko Tsurugaya, Daisuke Uchida, Akemi Matsushima, Kiyotaka OshikawaAbstract:Autoimmune Regulator (AIRE) is responsible for the development of organ-specific Autoimmune disease in a monogenic fashion. Rare and low levels of tissue expression together with the lack of AIRE-expressing cell lines have hampered a detailed analysis of the molecular dynamics of AIRE. Here we have established cell lines stably transfected with AIRE and studied the Regulatory mechanisms for its subcellular expression. We found that nuclear body (NB) formation by AIRE was dependent on the cell cycle. Biochemical fractionation revealed that a significant proportion of AIRE is associated with the nuclear matrix, which directs the functional domains of chromatin to provide sites for gene regulation. Upon proteasome inhibition, AIRE NBs were increased with concomitant reduced expression in the cytoplasm, suggesting that subcellular targeting of AIRE is regulated by a ubiquitin-proteasome pathway. We also found that AIRE NBs compete for cAMP-response element-binding protein-binding protein/p300, a common coactivator of transcription, with the promyelocytic leukemia gene product. These results suggest that the transcriptional regulating activities of AIRE within a cell are controlled and organized in a spatiotemporal manner.
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subcellular localization of the Autoimmune Regulator protein characterization of nuclear targeting and transcriptional activation domain
Journal of Biological Chemistry, 2001Co-Authors: Jukka Pitkanen, Perttu Vahamurto, Kai Krohn, Part PetersonAbstract:Abstract The Autoimmune Regulator (AIRE) gene, defective in the hereditary Autoimmune disease APECED, encodes a transcriptional Regulator protein. AIRE is expressed in the medullary epithelial cells and monocyte-dendritic cells of the thymus with lower expression in the spleen, fetal liver, and lymph nodes. At the cellular level, AIRE is located in microtubular structures of the cytoskeleton and in discrete nuclear dots resembling ND10 nuclear bodies. We studied the determinants of the targeting of AIRE into these structures. We report here that the N-terminal HSR domain confers localization to the microtubular network whereas the C-terminal region contains a second nuclear localization signal. We also demonstrate that the consensus nuclear localization signal of AIRE is functional and that the HSR domain harbors a nuclear export signal. Accordingly, the nuclear export inhibitor leptomycin B partially inhibits the nuclear export of AIRE. From a functional standpoint, we show that AIRE can activate the interferon β minimal promoter in a transfection assay and demonstrate that the transcriptional activating function of AIRE is mediated by its two plant homeodomain (PHD) zinc fingers.
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the Autoimmune Regulator protein has transcriptional transactivating properties and interacts with the common coactivator creb binding protein
Journal of Biological Chemistry, 2000Co-Authors: Jukka Pitkanen, Perttu Vahamurto, Vassilis Doucas, Kirsten Jensen, Satoko Aratani, Thomas Sternsdorf, Hans Will, Toshihiro Nakajima, Juha OllilaAbstract:Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, caused by mutations in the Autoimmune Regulator (AIRE) gene, is an autosomal recessive Autoimmune disease characterized by the breakdown of tolerance to organ-specific antigens. The 545 amino acid protein encoded by AIRE contains several structural motifs suggestive of a transcriptional Regulator and bears similarity to cellular proteins involved in transcriptional control. me show here that AIRE fused to a heterologous DNA binding domain activates transcription from a reporter promoter, and the activation seen requires the full-length protein or more than one activation domain. At the structural level AIRE forms homodimers through the NH2-terminal domain, and molecular modeling for this domain suggests a four-helix bundle structure. In agreement, we show that the common transcriptional coactivator CREB-binding protein (CBP) interacts with AIRE in vitro and in yeast nuclei through the CH1 and CH3 conserved domains. We suggest that the transcriptional transactivation properties of AIRE together with its interaction with CBP might be important in its function as disease-causing mutations almost totally abolish the activation effect. (Less)
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The Autoimmune Regulator protein has transcriptional transactivating properties and interacts with the common coactivator CREB-binding protein.
The Journal of biological chemistry, 2000Co-Authors: Jukka Pitkanen, Perttu Vahamurto, Vassilis Doucas, Juha Ollila, Kirsten Jensen, Satoko Aratani, Thomas Sternsdorf, Hans Will, Toshihiro Nakajima, Mauno VihinenAbstract:Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy, caused by mutations in the Autoimmune Regulator (AIRE) gene, is an autosomal recessive Autoimmune disease characterized by the breakdown of tolerance to organ-specific antigens. The 545 amino acid protein encoded by AIRE contains several structural motifs suggestive of a transcriptional Regulator and bears similarity to cellular proteins involved in transcriptional control. We show here that AIRE fused to a heterologous DNA binding domain activates transcription from a reporter promoter, and the activation seen requires the full-length protein or more than one activation domain. At the structural level AIRE forms homodimers through the NH(2)-terminal domain, and molecular modeling for this domain suggests a four-helix bundle structure. In agreement, we show that the common transcriptional coactivator CREB-binding protein (CBP) interacts with AIRE in vitro and in yeast nuclei through the CH1 and CH3 conserved domains. We suggest that the transcriptional transactivation properties of AIRE together with its interaction with CBP might be important in its function as disease-causing mutations almost totally abolish the activation effect.
Eystein S. Husebye - One of the best experts on this subject based on the ideXlab platform.
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Autoimmune Regulator and self tolerance molecular and clinical aspects
Immunological Reviews, 2016Co-Authors: Jakub Abramson, Eystein S. HusebyeAbstract:The establishment of central tolerance in the thymus is critical for avoiding deleterious Autoimmune diseases. Autoimmune Regulator (AIRE), the causative gene in Autoimmune polyendocrine syndrome type-1 (APS-1), is crucial for the establishment of self-tolerance in the thymus by promoting promiscuous expression of a wide array of tissue-restricted self-antigens. This step is critical for elimination of high-affinity self-reactive T cells from the immunological repertoire, and for the induction of a specific subset of Foxp3(+) T-Regulatory (Treg ) cells. In this review, we discuss the most recent advances in our understanding of how AIRE operates on molecular and cellular levels, as well as of how its loss of function results in breakdown of self-tolerance mechanisms characterized by a broad and heterogeneous repertoire of Autoimmune phenotypes.
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Autoimmune Regulator and self‐tolerance – molecular and clinical aspects
Immunological reviews, 2016Co-Authors: Jakub Abramson, Eystein S. HusebyeAbstract:The establishment of central tolerance in the thymus is critical for avoiding deleterious Autoimmune diseases. Autoimmune Regulator (AIRE), the causative gene in Autoimmune polyendocrine syndrome type-1 (APS-1), is crucial for the establishment of self-tolerance in the thymus by promoting promiscuous expression of a wide array of tissue-restricted self-antigens. This step is critical for elimination of high-affinity self-reactive T cells from the immunological repertoire, and for the induction of a specific subset of Foxp3(+) T-Regulatory (Treg ) cells. In this review, we discuss the most recent advances in our understanding of how AIRE operates on molecular and cellular levels, as well as of how its loss of function results in breakdown of self-tolerance mechanisms characterized by a broad and heterogeneous repertoire of Autoimmune phenotypes.
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Anti-cytokine autoantibodies suggest pathogenetic links with Autoimmune Regulator deficiency in humans and mice.
Clinical and experimental immunology, 2013Co-Authors: Jaanika Kärner, Eystein S. Husebye, Anette S. B. Wolff, Anthony Meager, Martti Laan, Julia Maslovskaja, Maire Pihlap, Anu Remm, Erkki Juronen, Katarina Trebušak PodkrajšekAbstract:Summary Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a recessive disorder resulting from mutations in the Autoimmune Regulator (AIRE). The patients' autoantibodies recognize not only multiple organ-specific targets, but also many type I interferons (IFNs) and most T helper type 17 (Th17) cell-associated cytokines, whose biological actions they neutralize in vitro. These anti-cytokine autoantibodies are highly disease-specific: otherwise, they have been found only in patients with thymomas, tumours of thymic epithelial cells that fail to express AIRE. Moreover, autoantibodies against Th17 cell-associated cytokines correlate with chronic mucocutaneous candidiasis in both syndromes. Here, we demonstrate that the immunoglobulin (Ig)Gs but not the IgAs in APECED sera are responsible for neutralizing IFN-ω, IFN-α2a, interleukin (IL)-17A and IL-22. Their dominant subclasses proved to be IgG1 and, surprisingly, IgG4 without IgE, possibly implicating Regulatory T cell responses and/or epithelia in their initiation in these AIRE-deficiency states. The epitopes on IL-22 and IFN-α2a appeared mainly conformational. We also found mainly IgG1 neutralizing autoantibodies to IL-17A in aged AIRE-deficient BALB/c mice – the first report of any target shared by these human and murine AIRE-deficiency states. We conclude that autoimmunization against cytokines in AIRE deficiency is not simply a mere side effect of chronic mucosal Candida infection, but appears to be related more closely to disease initiation.
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Autoimmune polyendocrine syndrome type 1 in Norway: phenotypic variation, autoantibodies, and novel mutations in the Autoimmune Regulator gene.
The Journal of clinical endocrinology and metabolism, 2006Co-Authors: Anette S. B. Wolff, Martina M. Erichsen, Kari Lima, Anne Grethe Myhre, Kristian J. Fougner, Anthony Meager, Ng’weina Francis Magitta, Jens Bollerslev, Per M. Knappskog, Eystein S. HusebyeAbstract:Context: The Autoimmune polyendocrine syndrome type I (APS I) is a rare disease that previously was difficult to diagnose. Autoantibody screening as well as mutational analysis of the disease gene Autoimmune Regulator (AIRE) are important diagnostic tools for this life-threatening syndrome. Objective: The objective of the study was to identify all patients with APS I in Norway and correlate their clinical features with their autoantibody profiles and mutations in the AIRE gene. Patients: We identified 36 Norwegian patients from 24 families with APS I (20 males, 16 females) during a nationwide survey for patients with Addison’s disease and polyendocrine syndromes, seven of them only after their death. Research Design and Methods: Clinical data were collected from questionnaires and patient records. AIRE mutations were determined by DNA sequencing. Most autoantibodies were measured in RIAs against recombinant autoantigens, but anti-type I interferon (IFN) antibodies were titrated in ELISA or antiviral inter...
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Mutational analysis of the Autoimmune Regulator (AIRE) gene in sporadic Autoimmune Addison's disease can reveal patients with unidentified Autoimmune polyendocrine syndrome type I.
European journal of endocrinology, 2002Co-Authors: Anette S. Bøe, Per M. Knappskog, Anne Grethe Myhre, Jan Inge Sorheim, Eystein S. HusebyeAbstract:Objective: To investigate whether patients with Addison‘s disease and polyendocrine syndromes have undiagnosed Autoimmune polyendocrine syndrome type I (APS I). Materials and methods: Forty patients with clinical manifestations resembling APS I and with autoantibodies typical of this condition were screened for Norwegian Autoimmune Regulator (AIRE) gene mutations. Results: A 30-year old man who had developed Addison’ s disease at the age of 12, but had no other components of APS I, was homozygous for the 1094 ‐ 1106 deletion mutation in exon 8 of the AIRE gene, the most common mutation found in Norway. Conclusions: APS I patients with milder and atypical phenotypes are difficult to diagnose on clinical grounds. Autoantibody analysis and mutational analysis of AIRE may therefore be helpful modalities for identifying these individuals.
Ana Rebane - One of the best experts on this subject based on the ideXlab platform.
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Autoimmune Regulator is acetylated by transcription coactivator cbp p300
Experimental Cell Research, 2012Co-Authors: Mario Saare, Ana Rebane, Balaji Rajashekar, Jaak Vilo, Part PetersonAbstract:The Autoimmune Regulator (AIRE) is a Regulator of transcription in the thymic medulla, where it controls the expression of a large set of peripheral-tissue specific genes. AIRE interacts with the transcriptional coactivator and acetyltransferase CBP and synergistically cooperates with it in transcriptional activation. Here, we aimed to study a possible role of AIRE acetylation in the modulation of its activity. We found that AIRE is acetylated in tissue culture cells and this acetylation is enhanced by overexpression of CBP and the CBP paralog p300. The acetylated lysines were located within nuclear localization signal and SAND domain. AIRE with mutations that mimicked acetylated K243 and K253 in the SAND domain had reduced transactivation activity and accumulated into fewer and larger nuclear bodies, whereas mutations that mimicked the unacetylated lysines were functionally similar to wild-type AIRE. Analogously to CBP, p300 localized to AIRE-containing nuclear bodies, however, the overexpression of p300 did not enhance the transcriptional activation of AIRE-regulated genes. Further studies showed that overexpression of p300 stabilized the AIRE protein. Interestingly, gene expression profiling revealed that AIRE, with mutations mimicking K243/K253 acetylation in SAND, was able to activate gene expression, although the affected genes were different and the activation level was lower from those regulated by wild-type AIRE. Our results suggest that the AIRE acetylation can influence the selection of AIRE activated genes.
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Autoimmune Regulator is acetylated by transcription coactivator CBP/p300
Experimental cell research, 2012Co-Authors: Mario Saare, Ana Rebane, Balaji Rajashekar, Jaak Vilo, Part PetersonAbstract:The Autoimmune Regulator (AIRE) is a Regulator of transcription in the thymic medulla, where it controls the expression of a large set of peripheral-tissue specific genes. AIRE interacts with the transcriptional coactivator and acetyltransferase CBP and synergistically cooperates with it in transcriptional activation. Here, we aimed to study a possible role of AIRE acetylation in the modulation of its activity. We found that AIRE is acetylated in tissue culture cells and this acetylation is enhanced by overexpression of CBP and the CBP paralog p300. The acetylated lysines were located within nuclear localization signal and SAND domain. AIRE with mutations that mimicked acetylated K243 and K253 in the SAND domain had reduced transactivation activity and accumulated into fewer and larger nuclear bodies, whereas mutations that mimicked the unacetylated lysines were functionally similar to wild-type AIRE. Analogously to CBP, p300 localized to AIRE-containing nuclear bodies, however, the overexpression of p300 did not enhance the transcriptional activation of AIRE-regulated genes. Further studies showed that overexpression of p300 stabilized the AIRE protein. Interestingly, gene expression profiling revealed that AIRE, with mutations mimicking K243/K253 acetylation in SAND, was able to activate gene expression, although the affected genes were different and the activation level was lower from those regulated by wild-type AIRE. Our results suggest that the AIRE acetylation can influence the selection of AIRE activated genes.
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the Autoimmune Regulator phd finger binds to non methylated histone h3k4 to activate gene expression
EMBO Reports, 2008Co-Authors: Tonis Org, Ana Rebane, Francesca Chignola, Csaba Hetenyi, Massimiliano Gaetani, Ingrid Liiv, Uko Maran, Luca Mollica, Matthew J Bottomley, Giovanna MuscoAbstract: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.
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Cooperative activation of transcription by Autoimmune Regulator AIRE and CBP.
Biochemical and biophysical research communications, 2005Co-Authors: Jukka Pitkanen, Ana Rebane, J. Rowell, Astrid Murumägi, Philipp Ströbel, Kaidi Möll, Mario Saare, J. Heikkilä, V. Doucas, Alexander MarxAbstract:Abstract Autoimmune Regulator (AIRE) is a transcriptional Regulator that is believed to control the expression of tissue-specific genes in the thymus. Mutated AIRE is responsible for onset of the hereditary Autoimmune disease APECED. AIRE is able to form nuclear bodies (NBs) and interacts with the ubiquitous transcriptional coactivator CBP. In this paper, we show that CBP and AIRE synergistically activate transcription on different promoter reporters whereas AIRE gene mutation R257X, found in APECED patients, interferes with this coactivation effect. Furthermore, the overexpression of AIRE and CBP collaboratively enhance endogenous IFNβ mRNA expression. The immunohistochemical studies suggest that CBP, depending on the balance of nuclear proteins, is a component of AIRE NBs. We also show that AIRE NBs are devoid of active chromatin and, therefore, not sites of transcription. In addition, we demonstrate by 3D analyses that AIRE and CBP, when colocalizing, are located spatially differently within AIRE NBs. In conclusion, our data suggest that AIRE activates transcription of the target genes, i.e., autoantigens in collaboration with CBP and that this activation occurs outside of AIRE NBs.
