The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance

Waterfield, Michael; Khan, Imran S.; Cortez, Jessica T; Fan, Una; Metzger, Todd C.; Greer, Alexandra M.; Fasano, Kayla J.; Martínez‐Llordella, Marc; Pollack, Joshua L.; Erle, David J.; Su, Maureen A.; Anderson, Mark S.

doi:10.1038/ni.2820

Cited by 80 publications

(82 citation statements)

References 49 publications

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“…The recognition of H3K4me0 is unlikely to constitute the sole and essential mechanism by which AIRE and its binding partners target TRAs (Zumer et al 2013), not least because AIRE co-opts the repressive ATF7IP-MBD1 complex for the induction of immunotolerance (Waterfield et al 2014). Our findings suggest that the TSS of many genes regulated by Aire expression in mature mTEC is characterized by the presence of H3K27me3 together with absent or low levels of H3K4me3.…”

Section: Genome Research 1927mentioning

confidence: 75%

Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia

et al. 2014

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Promiscuous gene expression (PGE) by thymic epithelial cells (TEC) is essential for generating a diverse T cell antigen receptor repertoire tolerant to self-antigens, and thus for avoiding autoimmunity. Nevertheless, the extent and nature of this unusual expression program within TEC populations and single cells are unknown. Using deep transcriptome sequencing of carefully identified mouse TEC subpopulations, we discovered a program of PGE that is common between medullary (m) and cortical TEC, further elaborated in mTEC, and completed in mature mTEC expressing the autoimmune regulator gene (Aire). TEC populations are capable of expressing up to 19,293 protein-coding genes, the highest number of genes known to be expressed in any cell type. Remarkably, in mouse mTEC, Aire expression alone positively regulates 3980 tissue-restricted genes. Notably, the tissue specificities of these genes include known targets of autoimmunity in human AIRE deficiency. Led by the observation that genes induced by Aire expression are generally characterized by a repressive chromatin state in somatic tissues, we found these genes to be strongly associated with H3K27me3 marks in mTEC. Our findings are consistent with AIRE targeting and inducing the promiscuous expression of genes previously epigenetically silenced by Polycomb group proteins. Comparison of the transcriptomes of 174 single mTEC indicates that genes induced by Aire expression are transcribed stochastically at low cell frequency. Furthermore, when present, Aire expression-dependent transcript levels were 16-fold higher, on average, in individual TEC than in the mTEC population.

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Section: Genome Research 1927mentioning

confidence: 75%

Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia

et al. 2014

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“…These two processes depend on the T cell receptor (TCR): self-peptide-MHC avidity and signal strength, where a weak signal leads to thymocyte survival (14), a strong signal leads to clonal deletion (15) and a moderate signal plus cytokines (IL-2) leads to nTreg differentiation (16, 17). The efficiencies of negative selection and the differentiation of nTregs are dependent on the production and presentation of tissue-specific antigens (TSAs) on MHC, which is, in part, regulated by the autoimmune regulator gene ( Aire) in mTECs (18–22). …”

Section: Introductionmentioning

confidence: 99%

Thymic Involution Perturbs Negative Selection Leading to Autoreactive T Cells That Induce Chronic Inflammation

Coder

Wang

Ruan

et al. 2015

The Journal of Immunology

101

114

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Thymic involution and the subsequent amplified release of autoreactive T cells increase the susceptibility toward developing autoimmunity, but whether they induce chronic inflammation with advanced age remains unclear. The presence of chronic low-level pro-inflammatory factors in elderly individuals (termed inflammaging) is a significant risk factor for morbidity and mortality in virtually every chronic age-related disease. To determine how thymic involution leads to the persistent release and activation of autoreactive T cells capable of inducing inflammaging, we used a FoxN1 conditional knockout (FoxN1-cKO) mouse model that induces accelerated thymic involution while maintaining a young periphery. We found that thymic involution leads to T cell activation shortly after thymic egress, which is accompanied by a chronic inflammatory phenotype consisting of cellular infiltration into non-lymphoid tissues, increased TNFα production and elevated serum IL-6. Autoreactive T cell clones were detected in the periphery of FoxN1-cKO mice. A failure of negative selection, facilitated by decreased expression of Aire rather than impaired regulatory T cell (Treg) generation, led to autoreactive T cell generation. Furthermore, the young environment can reverse age-related Treg accumulation in naturally aged mice, but not inflammatory infiltration. Together, these findings identify thymic involution and the persistent activation of autoreactive T cells as a contributing source of chronic inflammation (inflammaging).

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“…To date, the only known molecular determinant driving pGE in the thymus is the autoimmune regulator (AIRE), a transcriptional regulator that does not act as a conventional transcription factor (10)(11)(12). AIRE interacts with repressive epigenetic marks and recruits proteins that promote transcriptional elongation and pre-mRNA processing (13,14). In addition to its role in promoting the expression of TRA for the purpose of negative selection (10), AIRE also affects mTEC development (15), enhances Ag presentation to thymocytes (16), and regulates Ag transfer from mTEC to dendritic cells (DCs) (17).…”

mentioning

confidence: 99%

Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells

St-Pierre

Trofimov

Brochu

et al. 2015

The Journal of Immunology

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Establishment of self-tolerance in the thymus depends on promiscuous expression of tissue-restricted Ags (TRA) by thymic epithelial cells (TEC). This promiscuous gene expression (pGE) is regulated in part by the autoimmune regulator (AIRE). To evaluate the commonalities and discrepancies between AIRE-dependent and -independent pGE, we analyzed the transcriptome of the three main TEC subsets in wild-type and Aire knockout mice. We found that the impact of AIRE-dependent pGE is not limited to generation of TRA. AIRE decreases, via non–cell autonomous mechanisms, the expression of genes coding for positive regulators of cell proliferation, and it thereby reduces the number of cortical TEC. In mature medullary TEC, AIRE-driven pGE upregulates non-TRA coding genes that enhance cell–cell interactions (e.g., claudins, integrins, and selectins) and are probably of prime relevance to tolerance induction. We also found that AIRE-dependent and -independent TRA present several distinctive features. In particular, relative to AIRE-induced TRA, AIRE-independent TRA are more numerous and show greater splicing complexity. Furthermore, we report that AIRE-dependent versus -independent TRA project nonredundant representations of peripheral tissues in the thymus.

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The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance

Cited by 80 publications

References 49 publications

Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia

Population and single-cell genomics reveal the Aire dependency, relief from Polycomb silencing, and distribution of self-antigen expression in thymic epithelia

Thymic Involution Perturbs Negative Selection Leading to Autoreactive T Cells That Induce Chronic Inflammation

Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells

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