Transcriptional programs that control expression of the autoimmune regulator gene Aire

Herzig, Yonatan; Nevo, Shir; Bornstein, Chamutal; Brezis, M; Ben-Hur, Sharon; Shkedy, Aya; Eisenberg-Bord, Michal; Levi, Ben; Delacher, Michael; Goldfarb, Yael; David, Eyal; Weinberger, Leehee; Viukov, Sergey; Ben‐Dor, Shifra; Giraud, Matthieu; Hanna, Jacob; Breiling, Achim; Lyko, Frank; Amit, Ido; Feuerer, Markus; Abramson, Jakub

doi:10.1038/ni.3638

Cited by 56 publications

(56 citation statements)

References 38 publications

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“…Moreover, the lysyl‐hydroxylase Jmjd6 (Jumonji domain‐containing protein 6) affects splicing of intron 2 of the Aire gene and is required for expression of mature Aire in mTECs, and Dgcr8 (DiGeorge syndrome critical region gene 8) is important for accumulation of Aire‐expressive mTECs in the thymus . Recent work from Herzig et al further demonstrated a very complex method of Aire expression regulation resulting from positive and negative mechanisms and the coordinated effort of multiple transcription factors, Irf4, Irf8, Tbx21, Tcf7, and Ctcfl. Whether patients with APECED‐like clinical disease with wildtype AIRE genotype have mutations in the aforementioned AIRE partners and regulators remains to be determined in future studies.…”

Section: Aire Partners and Regulationmentioning

confidence: 99%

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

Constantine

Lionakis

2018

Immunological Reviews

128

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Summary: The discovery of the Autoimmune Regulator (AIRE) protein and the delineation of its critical contributions in the establishment of central immune tolerance has significantly expanded our understanding of the immunological mechanisms that protect from the development of autoimmune disease. The parallel identification and characterization of patient cohorts with the monogenic disorder Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), which is typically caused by biallelic AIRE mutations, has underscored the critical contribution of AIRE in fungal immune surveillance at mucosal surfaces and in prevention of multiorgan autoimmunity in humans. In this review, we synthesize the current clinical, genetic, molecular and immunological knowledge derived from basic studies in Aire-deficient animals and from APECED patient cohorts. We also outline major advances and research endeavors that show promise for informing improved diagnostic and therapeutic approaches for patients with APECED.

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Section: Aire Partners and Regulationmentioning

confidence: 99%

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

Constantine

Lionakis

2018

Immunological Reviews

128

View full text Add to dashboard Cite

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“…Additionally, there are proteins that, despite not interacting with AIRE, participate in the transcriptional complex associated with the expression of PTAs in mTECs . Many of these molecules even regulate Aire itself …”

Section: Controlling the Expression Of Peripheral Tissue Antigensmentioning

confidence: 99%

“…10 Many of these molecules even regulate Aire itself. 47 Recently, the group of Benoist/Mathis at Harvard University in Boston, MA, have found that some AIRE partners, especially those associated with the DNAdamage response, localize preferentially on chromatin sections known as super-enhancers, as for example TOPO 1. 48 In summary, Aire leads to the activation of PGE in mTECs when it is recruited into the transcriptional start sites (TSS) of most genes.…”

Section: Controlling the Expression Of Peripheral Tissue Antigensmentioning

confidence: 99%

Update on Aire and thymic negative selection

et al. 2017

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SummaryTwenty years ago, the autoimmune regulator (Aire) gene was associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, and was cloned and sequenced. Its importance goes beyond its abstract link with human autoimmune disease. Aire identification opened new perspectives to better understand the molecular basis of central tolerance and self-non-self distinction, the main properties of the immune system. Since 1997, a growing number of immunologists and molecular geneticists have made important discoveries about the function of Aire, which is essentially a pleiotropic gene. Aire is one of the functional markers in medullary thymic epithelial cells (mTECs), controlling their differentiation and expression of peripheral tissue antigens (PTAs), mTEC-thymocyte adhesion and the expression of microRNAs, among other functions. With Aire, the immunological tolerance became even more apparent from the molecular genetics point of view. Currently, mTECs represent the most unusual cells because they express almost the entire functional genome but still maintain their identity. Due to the enormous diversity of PTAs, this uncommon gene expression pattern was termed promiscuous gene expression, the interpretation of which is essentially immunological -i.e. it is related to self-representation in the thymus. Therefore, this knowledge is strongly linked to the negative selection of autoreactive thymocytes. In this update, we focus on the most relevant results of Aire as a transcriptional and post-transcriptional controller of PTAs in mTECs, its mechanism of action, and its influence on the negative selection of autoreactive thymocytes as the bases of the induction of central tolerance and prevention of autoimmune diseases.

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“…24,26,29 Granulocyte macrophage colony-stimulating factor–driven moDC differentiation requires expression of functional IRF4 and CEBPB. 56,62,67,74 CEBPB can promote moDC differentiation by counteracting IRF8 effects. 67 Notably, KLF4 induces a set of monocyte lineage–associated molecules and is a key switch factor regulating differentiation of monocytes into moDCs.…”

Section: Transcription Factors and Generation Of Distinct DC Subsetsmentioning

confidence: 99%

Epigenetic Regulation of Dendritic Cell Development and Function

Tian¹,

Meng²,

Zhang³

2017

Cancer J

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The immune system is characterized by the generation of structurally and functionally heterogeneous immune cells that constitute complex innate and adaptive immunity. This heterogeneity of immune cells results from changes in the expression of genes without altering DNA sequence. To achieve this heterogeneity, immune cells orchestrate the expression and functional status of transcription factor (TF) networks, which can be broadly categorized into 3 classes: pioneer TFs that facilitate initial commitment and differentiation of hematopoietic cells, subset-specific TFs that promote the generation of selected cell lineages, and immune-signaling TFs that regulate specialized function in differentiated cells. Epigenetic mechanisms are known to be critical for organizing the TF networks, thereby controlling immune cell lineage-fate decisions, plasticity, and function. The effects of epigenetic regulators can be heritable during cell mitosis, primarily through the modification of DNA and histone methylation patterns at gene loci. By doing so, the immune system is enabled to mount a selective but robust response to stimuli, such as pathogens, tumor cells, autoantigens, or allogeneic antigens in the setting of transplantation, while preserving the immune cell reservoir necessary for protecting the host against numerous other unexpected stimuli and limit detrimental effect of systemic inflammatory reactions.

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Transcriptional programs that control expression of the autoimmune regulator gene Aire

Cited by 56 publications

References 38 publications

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

Update on Aire and thymic negative selection

Epigenetic Regulation of Dendritic Cell Development and Function

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