Inflammation and Hyperglycemia Mediate <i>Deaf1</i> Splicing in the Pancreatic Lymph Nodes via Distinct Pathways During Type 1 Diabetes

Yip, Linda; Fuhlbrigge, Rebecca; Taylor, C. V.; Creusot, Rémi J.; Nishikawa-Matsumura, Teppei; Whiting, Chan C.; Schartner, Jill; Akter, Raushanara; Herrath, Matthias von; Fathman, C. Garrison

doi:10.2337/db14-0803

Cited by 22 publications

(19 citation statements)

References 48 publications

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“…Deformed epidermal autoregulatory factor 1 (Deaf1) is a transcriptional regulator that controls the expression of peripheral tissue antigens in lymph node stromal cells; these peripheral tissue antigens are important to ‘educate’ T regulatory cells (Tregs) and maintain tolerance (89). Deaf1 is spliced into a dominant negative variant (Deaf1–Var1) in pancreatic lymph nodes of T1D patients (89), and Deaf1–Var1 expression is reduced in the pancreatic lymph nodes of diabetes-prone NOD mice that escape diabetes development (90). Inflammation and hyperglycaemia drive Deaf1 splicing independently through activation of two different splicing factors, Srsf10 and Ptbp2 respectively (90).…”

Section: β Cell Death In Type 1 Diabetes and The Role Of Asmentioning

confidence: 99%

“…Deaf1 is spliced into a dominant negative variant (Deaf1–Var1) in pancreatic lymph nodes of T1D patients (89), and Deaf1–Var1 expression is reduced in the pancreatic lymph nodes of diabetes-prone NOD mice that escape diabetes development (90). Inflammation and hyperglycaemia drive Deaf1 splicing independently through activation of two different splicing factors, Srsf10 and Ptbp2 respectively (90). These data suggest a complementary role for AS in the regulation of auto-immunity: since deletional tolerance and induction of Tregs is at least in part mediated by expression of peripheral tissue antigens, Deaf1 splicing and consequent decrease in function may allow the persistence of an increased number of autoreactive T cells, thus aggravating the autoimmune attack against β cells (90).…”

Section: β Cell Death In Type 1 Diabetes and The Role Of Asmentioning

confidence: 99%

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MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research

Juan-Mateu

Villate

Eizirik

2016

European Journal of Endocrinology

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Type 1 diabetes (T1D) is a chronic autoimmune disease in which pancreatic β cells are killed by infiltrating immune cells and by cytokines released by these cells. This takes place in the context of a dysregulated dialogue between invading immune cells and target β cells, but the intracellular signals that decide β cell fate remain to be clarified. Alternative splicing (AS) is a complex post-transcriptional regulatory mechanism affecting gene expression. It regulates the inclusion/exclusion of exons into mature mRNAs, allowing individual genes to produce multiple protein isoforms that expand the proteome diversity. Functionally related transcript populations are co-ordinately spliced by master splicing factors, defining regulatory networks that allow cells to rapidly adapt their transcriptome in response to intra and extracellular cues. There is a growing interest in the role of AS in autoimmune diseases, but little is known regarding its role in T1D. In this review, we discuss recent findings suggesting that splicing events occurring in both immune and pancreatic β cells contribute to the pathogenesis of T1D. Splicing switches in Tcells and in lymph node stromal cells are involved in the modulation of the immune response against β cells, while β cells exposed to pro-inflammatory cytokines activate complex splicing networks that modulate β cell viability, expression of neoantigens and susceptibility to immune-induced stress. Unveiling the role of AS in β cell functional loss and death will increase our understanding of T1D pathogenesis and may open new avenues for disease prevention and therapy.

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Section: β Cell Death In Type 1 Diabetes and The Role Of Asmentioning

confidence: 99%

Section: β Cell Death In Type 1 Diabetes and The Role Of Asmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research

Juan-Mateu

Villate

Eizirik

2016

European Journal of Endocrinology

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“…DEAF1 is spliced into two different isoforms DEAF1 and a dominant negative isoform DEAF1-Var1. The expression level of DEAF-Var1 correlates with disease severity in NOD mice and the expression level of DEAF1-Var is reduced in NOD mice that do not develop diabetes (Yip et al 2015).…”

Section: Deaf-1mentioning

confidence: 99%

“…The surface antigens whose expression is controlled by DEAF1 are needed for T cells to Thomas et al (2009) CD8+ T cells cytotoxic T lymphocytes Perforin and granzyme B Granule-mediated cytotoxicity is the dominant mechanism of killing β cells by CTL. Granzyme B activates the pro-apoptotic molecule Bid Dudek et al (2006) CD4+ T cells cytotoxic T lymphocytes Thomas et al (2009) Interleukin-1 (IL-1) IFNc and TNF Cytokines activate NF-κB and STAT1 transcription factors, which induce nitric oxide synthase (iNOS) and production of toxic free radical NO Darville and Eizirik (1998) β 'learn' to recognise pathogens (Yip et al 2015). DEAF1 is spliced into two different isoforms DEAF1 and a dominant negative isoform DEAF1-Var1.…”

Section: Deaf-1mentioning

confidence: 99%

Abnormalities in alternative splicing in diabetes: therapeutic targets

Dlamini

Mokoena

Hull

2017

Journal of Molecular Endocrinology

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Diabetes mellitus (DM) is a non-communicable, metabolic disorder that affects 416 million individuals worldwide. Type 2 diabetes contributes to a vast 85-90% of the diabetes incidences while 10-15% of patients suffer from type 1 diabetes. These two predominant forms of DM cause a significant loss of functional pancreatic β-cell mass causing different degrees of insulin deficiency, most likely, due to increased β-cell apoptosis. Treatment options involve the use of insulin sensitisers, α-glucosidase inhibitors, and β-cell secretagogues which are often expensive, limited in efficacy and carry detrimental adverse effects. Cost-effective options for treatment exists in the form of herbal drugs, however, scientific validations of these widely used medicinal plants are still underway. Alternative splicing (AS) is a co-ordinated post-transcriptional process in which a single gene generates multiple mRNA transcripts which results in increased amounts of functionally different protein isoforms and in some cases aberrant splicing leads to metabolic disease. In this review, we explore the association of AS with metabolic alterations in DM and the biological significance of the abnormal splicing of some pathogenic diabetes-related genes. An understanding of the molecular mechanism behind abnormally spliced transcripts will aid in the development of new diagnostic, prognostic and therapeutic tools.

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“…LNSCs also have been suggested to mediate the conversion of autoreactive CD4 + T cells to Tregs [14]. Yip L. (2015) showed that Deaf1 controls the transcription of hundreds of genes in the pancreatic lymph nodes (PLNs) and regulates the processing and presentation of PTA genes in LNSCs [15]. Therefore, the aim of our study was to determine the effect of the levels of Deaf1 and Aire mRNA expression on the nature of Foxp3 + Treg cells differentiation during experimental STZ-induced diabetes mellitus (EDM) in rats PLN.…”

Section: Introductionmentioning

confidence: 99%

Breakdown in Peripheral Immune Tolerance in Experimental Diabetes Mellitus

Kamyshny¹,

Путилин²,

Kamyshna³

2016

J Mol Pathophysiol

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Background: Peripheral tolerance can be mediated by extrathymic Aire-expressing cells (eTACs) and lymph node stromal cells (LNSCs) have recently been shown to induce T-cell tolerance by ectopically expressing and presenting range of peripheral tissue antigens (PTAs). New evidence shows that all types of LNSCs-including fibroblastic reticular cells, follicular DCs, and lymphatic endothelial cells-express PTAs. Ectopic expression of genes encoding PTAs in lymph nodes (LN) controlled by transcriptional regulators Aire and deformed autoregulatory factor 1 (Deaf1). Therefore, the aim of our study was to determine the effect of the levels of Deaf1 and Aire mRNA expression on the nature of Foxp3 + Treg cells differentiation during experimental STZ-induced diabetes mellitus (EDM) in rats pancreatic lymph nodes (PLN). Methods. To determine the level of mRNA Deaf1 and Aire expression was performed RT-PCR in real-time by thermocycler CFX96™ Real-Time PCR Detection Systems. The relative level of gene expression were studied with rat reference genes GAPDH by the method ΔΔ Ct. Statistical analysis were conducted using available software «Bio-Rad СFX Manager 3.1». The Foxp3 +immunopositive lymphocytes were determined using an indirect immunofluorescence technique with using a monoclonal rat antibody. Results: Development of EDM was accompanied by decreased the expression levels of the transcriptional regulator Deaf1 and Aire in rats PLN. So, Deaf1 expression is decreased 4,2-fold in rats PLN with 3-week EDM and 2,5fold in rats with 5-week EDM. Aire expression is decreased 2-fold in rats PLN with 3-week EDM and 50-fold in rats with 5-week EDM. Reduced Deaf1 and Aire mRNA expression during EDM associated with an decreased of total amount of Treg in the PLN, led to changes of distribution into individual classes of FoxP3 + lymphocytes and FoxP3 concentration in immunopositive cells. Conclusions: development of EDM due to a breakdown in peripheral immune tolerance. This contributes to progression of diabetes mellitus.

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Inflammation and Hyperglycemia Mediate Deaf1 Splicing in the Pancreatic Lymph Nodes via Distinct Pathways During Type 1 Diabetes

Cited by 22 publications

References 48 publications

MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research

MECHANISMS IN ENDOCRINOLOGY: Alternative splicing: the new frontier in diabetes research

Abnormalities in alternative splicing in diabetes: therapeutic targets

Breakdown in Peripheral Immune Tolerance in Experimental Diabetes Mellitus

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