Rapid chromatin repression by Aire provides precise control of immune tolerance

Koh, Andrew S.; Miller, Erik L.; Buenrostro, Jason D.; Moskowitz, David M.; Wang, Jing; Greenleaf, William J.; Chang, Howard Y.; Crabtree, Robert H.

doi:10.1038/s41590-017-0032-8

Cited by 54 publications

(78 citation statements)

References 70 publications

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“…However, supportive evidence that this might be expected to be the case was provided by the observation, which we have expanded upon in this study, that the chromatin patterns around AIRE-induced genes in mouse ENCODE ChIP-seq data derived from non-TEC cell types are similar to those observed in mTEC hi ( 3 ). This suggests that AIRE is not required to establish the chromatin architecture of tissue specific antigens but instead acts dynamically to ensure appropriate levels of histone modifications, as suggested by a previous chromatin in vivo assay ( 8 ). Our machine learning approaches support the fact that AIRE status can be predicted from chromatin signatures in both mTEC lo and mTEC hi .…”

Section: Discussionmentioning

confidence: 83%

“…Mutations in AIRE result in the development of multi-system autoimmune disease in humans ( 5 ). Recently other genes, including Fezf2, Prdm1 , and Brg1 , have also been identified to regulate PGE ( 6 – 8 ).…”

Section: Introductionmentioning

confidence: 99%

“…Patterns of tissue specific gene expression are known to occur independent of changes in DNA methylation ( 10 ). AIRE dynamically remodels chromatin to reduce chromatin accessibility and to tune the level of promiscuous gene expression across tissue specific genes ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

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Comprehensively Profiling the Chromatin Architecture of Tissue Restricted Antigen Expression in Thymic Epithelial Cells Over Development

et al. 2018

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Thymic epithelial cells (TEC) effect crucial roles in thymopoiesis including the control of negative thymocyte selection. This process depends on their capacity to express promiscuously genes encoding tissue-restricted antigens. This competence is accomplished in medullary TEC (mTEC) in part by the presence of the transcriptional facilitator AutoImmune REgulator, AIRE. AIRE-regulated gene transcription is marked by repressive chromatin modifications, including H3K27me3. When during TEC development these chromatin marks are established, however, remains unclear. Here we use a comprehensive ChIP-seq dataset of multiple chromatin modifications in different TEC subtypes to demonstrate that the chromatin landscape is established early in TEC differentiation. Much of the chromatin architecture found in mature mTEC was found to be present already over earlier stages of mTEC lineage differentiation as well as in non-TEC tissues. This was reflected by the fact that a machine learning approach accurately classified genes as AIRE-induced or AIRE-independent both in immature and mature mTEC. Moreover, analysis of TEC specific enhancer elements identified candidate transcription factors likely to be important in mTEC development and function. Our findings indicate that the mature mTEC chromatin landscape is laid down early in mTEC differentiation, and that AIRE is not required for large-scale re-patterning of chromatin in mTEC.

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Section: Discussionmentioning

confidence: 83%

Section: Introductionmentioning

confidence: 99%

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Comprehensively Profiling the Chromatin Architecture of Tissue Restricted Antigen Expression in Thymic Epithelial Cells Over Development

et al. 2018

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“…Aire binds only weakly and nonspecifically to DNA, and no common sequence motif has been identified for Aire target genes 11,12 . Recent chromatin immunoprecipitation experiments suggest that Aire recognizes general epigenetic features and alters chromatin structure including superenhancer and Polycomb-repressed regions, which may lead to indirect regulation of multiple target genes [13][14][15][16] . This idea is further supported by the stochastic nature of target gene expression at a single cell level 15,17,18 , and the variance of Aire-dependent target genes depending on the cell type 19 .…”

mentioning

confidence: 99%

Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance

Huoh

Park

et al. 2020

Nat Commun

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Aggregate-like biomolecular assemblies are emerging as new conformational states with functionality. Aire, a transcription factor essential for central T cell tolerance, forms large aggregate-like assemblies visualized as nuclear foci. Here we demonstrate that Aire utilizes its caspase activation recruitment domain (CARD) to form filamentous homo-multimers in vitro, and this assembly mediates foci formation and transcriptional activity. However, CARD-mediated multimerization also makes Aire susceptible to interaction with promyelocytic leukemia protein (PML) bodies, sites of many nuclear processes including protein quality control of nuclear aggregates. Several loss-of-function Aire mutants, including those causing autoimmune polyendocrine syndrome type-1, form foci with increased PML body association. Directing Aire to PML bodies impairs the transcriptional activity of Aire, while dispersing PML bodies with a viral antagonist restores this activity. Our study thus reveals a new regulatory role of PML bodies in Aire function, and highlights the interplay between nuclear aggregate-like assemblies and PML-mediated protein quality control.

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“…Aire has been demonstrated to contribute to the establishment of self-tolerance by optimizing the expression of TRAs by mTECs by employing various transcriptional pathways in a cell-intrinsic manner (14,37,38). The present study has revealed a novel mechanism by which heterogeneity and/or diversity of mTECs can be also created in an Aire-dependent but cell-extrinsic manner: Aire + mTECs functioned in trans to maintain Ly-6C/Ly-6G + mTECs.…”

Section: Discussionmentioning

confidence: 65%

Aire Controls in Trans the Production of Medullary Thymic Epithelial Cells Expressing Ly-6C/Ly-6G

Morimoto

Nishikawa

Kakimoto

et al. 2018

The Journal of Immunology

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Medullary thymic epithelial cells (mTECs), which express a wide range of tissue-restricted Ags (TRAs), contribute to the establishment of self-tolerance by eliminating autoreactive T cells and/or inducing regulatory T cells. Aire controls a diverse set of TRAs within Aire-expressing cells by employing various transcriptional pathways. As Aire has a profound effect on transcriptomes of mTECs, including TRAs not only at the single-cell but also the population level, we suspected that Aire (Aire+ mTECs) might control the cellular composition of the thymic microenvironment. In this study, we confirmed that this is indeed the case by identifying a novel mTEC subset expressing Ly-6 family protein whose production was defective in Aire-deficient thymi. Reaggregated thymic organ culture experiments demonstrated that Aire did not induce the expression of Ly-6C/Ly-6G molecules from mTECs as Aire-dependent TRAs in a cell-intrinsic manner. Instead, Aire+ mTECs functioned in trans to maintain Ly-6C/Ly-6G+ mTECs. Thus, Aire not only controls TRA expression transcriptionally within the cell but also controls the overall composition of mTECs in a cell-extrinsic manner, thereby regulating the transcriptome from mTECs on a global scale.

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Rapid chromatin repression by Aire provides precise control of immune tolerance

Cited by 54 publications

References 70 publications

Comprehensively Profiling the Chromatin Architecture of Tissue Restricted Antigen Expression in Thymic Epithelial Cells Over Development

Comprehensively Profiling the Chromatin Architecture of Tissue Restricted Antigen Expression in Thymic Epithelial Cells Over Development

Dual functions of Aire CARD multimerization in the transcriptional regulation of T cell tolerance

Aire Controls in Trans the Production of Medullary Thymic Epithelial Cells Expressing Ly-6C/Ly-6G

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