Deaf1 isoforms control the expression of genes encoding peripheral tissue antigens in the pancreatic lymph nodes during type 1 diabetes

Yip, Linda; Su, Leon; Sheng, Deqiao; Chang, Pearl; Atkinson, Mark A.; Czesak, Margaret; Albert, Paul R.; Collier, Ai‐ris Y.; Turley, Shannon J.; Fathman, C. Garrison; Creusot, Rémi J.

doi:10.1038/ni.1773

Cited by 127 publications

(147 citation statements)

References 32 publications

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“…5E), raising the interesting possibility that translational rhythmicity is propagated to transcriptional target genes and thus contributes to shaping the rhythmic transcriptome. In accordance, previously reported DEAF1 targets (Yip et al 2009) were significantly enriched for genes that are rhythmically transcribed (enrichment 1.6-fold; P = 0.009) ( Fig. 5F; identified by Du et al 2014).…”

Section: Widespread Time Of Day-dependent Translation Of Nonrhythmic supporting

confidence: 73%

Ribosome profiling reveals the rhythmic liver translatome and circadian clock regulation by upstream open reading frames

et al. 2015

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Mammalian gene expression displays widespread circadian oscillations. Rhythmic transcription underlies the core clock mechanism, but it cannot explain numerous observations made at the level of protein rhythmicity. We have used ribosome profiling in mouse liver to measure the translation of mRNAs into protein around the clock and at high temporal and nucleotide resolution. We discovered, transcriptome-wide, extensive rhythms in ribosome occupancy and identified a core set of approximately 150 mRNAs subject to particularly robust daily changes in translation efficiency. Cycling proteins produced from nonoscillating transcripts revealed thus-far-unknown rhythmic regulation associated with specific pathways (notably in iron metabolism, through the rhythmic translation of transcripts containing iron responsive elements), and indicated feedback to the rhythmic transcriptome through novel rhythmic transcription factors. Moreover, estimates of relative levels of core clock protein biosynthesis that we deduced from the data explained known features of the circadian clock better than did mRNA expression alone. Finally, we identified uORF translation as a novel regulatory mechanism within the clock circuitry. Consistent with the occurrence of translated uORFs in several core clock transcripts, loss-of-function of Denr, a known regulator of reinitiation after uORF usage and of ribosome recycling, led to circadian period shortening in cells. In summary, our data offer a framework for understanding the dynamics of translational regulation, circadian gene expression, and metabolic control in a solid mammalian organ.

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Section: Widespread Time Of Day-dependent Translation Of Nonrhythmic supporting

confidence: 73%

Ribosome profiling reveals the rhythmic liver translatome and circadian clock regulation by upstream open reading frames

et al. 2015

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“…This function extends the importance of lymph node stromal cells for the immune system [9,24,[63][64][65][66][67][68][69][70]. The identified antigen-presenting stromal cells can be found within the GP38 pos CD31 neg and GP38 neg CD31 neg stromal cell subsets, and additionally bind the lectin Ulex europaeus agglutinin-1 or express epithelial cell adhesion molecule, respectively [65,66].…”

Section: Box 1 Lymph Node Stromal Cell Subsetsmentioning

confidence: 92%

Interdependence of stromal and immune cells for lymph node function

Koning

Mebius

2012

Trends in Immunology

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“…In the absence of Deaf1 in the nucleus, the transcription of TSAs (tissue-specific antigens) is reduced. In NOD mice undergoing destructive insulitis, Deaf1-VAR is in excess and the expression of TSAs are consequently downregulated [113]. Reduced expression of Deaf1 was also found in T1D patients.…”

Section: Activationmentioning

confidence: 96%

Advances in our understanding of the pathophysiology of Type 1 diabetes: lessons from the NOD mouse

2013

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T1D (Type 1 diabetes) is an autoimmune disease caused by the immune-mediated destruction of pancreatic β-cells. Studies in T1D patients have been limited by the availability of pancreatic samples, a protracted pre-diabetic phase and limitations in markers that reflect β-cell mass and function. The NOD (non-obese diabetic) mouse is currently the best available animal model of T1D, since it develops disease spontaneously and shares many genetic and immunopathogenic features with human T1D. Consequently, the NOD mouse has been extensively studied and has made a tremendous contribution to our understanding of human T1D. The present review summarizes the key lessons from NOD mouse studies concerning the genetic susceptibility, aetiology and immunopathogenic mechanisms that contribute to autoimmune destruction of β-cells. Finally, we summarize the potential and limitations of immunotherapeutic strategies, successful in NOD mice, now being trialled in T1D patients and individuals at risk of developing T1D.

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Deaf1 isoforms control the expression of genes encoding peripheral tissue antigens in the pancreatic lymph nodes during type 1 diabetes

Cited by 127 publications

References 32 publications

Ribosome profiling reveals the rhythmic liver translatome and circadian clock regulation by upstream open reading frames

Ribosome profiling reveals the rhythmic liver translatome and circadian clock regulation by upstream open reading frames

Interdependence of stromal and immune cells for lymph node function

Advances in our understanding of the pathophysiology of Type 1 diabetes: lessons from the NOD mouse

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