Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome

Nica, Alexandra C.; Ongen, Halit; Irminger, Jean-Claude; Bosco, Domenico; Berney, Thierry; Antonarakis, Stylianos E.; Halban, Philippe A.; Dermitzakis, Emmanouil T.

doi:10.1101/gr.150706.112

Cited by 170 publications

(274 citation statements)

References 43 publications

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“…The b-cells express and release cytokines and chemokines, providing a link between the b-cell and the immune system in early T1D (8). However, these studies are based on a few cases of disease, including tissue obtained mainly from subjects with long-standing T1D (6,7).…”

mentioning

confidence: 99%

Function of Isolated Pancreatic Islets From Patients at Onset of Type 1 Diabetes: Insulin Secretion Can Be Restored After Some Days in a Nondiabetogenic Environment In Vitro

et al. 2015

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The understanding of the etiology of type 1 diabetes (T1D) remains limited. One objective of the Diabetes Virus Detection (DiViD) study was to collect pancreatic tissue from living subjects shortly after the diagnosis of T1D. Here we report the insulin secretion ability by in vitro glucose perifusion and explore the expression of insulin pathway genes in isolated islets of Langerhans from these patients. Whole-genome RNA sequencing was performed on islets from six DiViD study patients and two organ donors who died at the onset of T1D, and the findings were compared with those from three nondiabetic organ donors. All human transcripts involved in the insulin pathway were present in the islets at the onset of T1D. Glucose-induced insulin secretion was present in some patients at the onset of T1D, and a perfectly normalized biphasic insulin release was obtained after some days in a nondiabetogenic environment in vitro. This indicates that the potential for endogenous insulin production is good, which could be taken advantage of if the disease process was reversed at diagnosis.

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mentioning

confidence: 99%

Function of Isolated Pancreatic Islets From Patients at Onset of Type 1 Diabetes: Insulin Secretion Can Be Restored After Some Days in a Nondiabetogenic Environment In Vitro

et al. 2015

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“…Therefore, combination of DNA and RNA sequencing in the same individuals may help to disentangle the role these SNPs play in the pathogenesis of the disease (8). Although the human pancreatic islet transcriptome has been previously described (6,(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), using microarrays or RNA sequencing of a limited number of nondiabetic individuals, this has not allowed a more global analysis of the complexity of the islet transcriptome in T2D. Here we combined genotypic imputation, expression microarrays, and exome and RNA sequencing (ExomeSeq and RNA-Seq) in a large number of human pancreatic islets from deceased donors with and without T2D.…”

mentioning

confidence: 99%

Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism

Fadista

Vikman

Laakso

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

423

535

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Genetic variation can modulate gene expression, and thereby phenotypic variation and susceptibility to complex diseases such as type 2 diabetes (T2D). Here we harnessed the potential of DNA and RNA sequencing in human pancreatic islets from 89 deceased donors to identify genes of potential importance in the pathogenesis of T2D. We present a catalog of genetic variants regulating gene expression (eQTL) and exon use (sQTL), including many long noncoding RNAs, which are enriched in known T2D-associated loci. Of 35 eQTL genes, whose expression differed between normoglycemic and hyperglycemic individuals, siRNA of tetraspanin 33 (TSPAN33), 5′-nucleotidase, ecto (NT5E), transmembrane emp24 protein transport domain containing 6 (TMED6), and p21 protein activated kinase 7 (PAK7) in INS1 cells resulted in reduced glucose-stimulated insulin secretion. In addition, we provide a genome-wide catalog of allelic expression imbalance, which is also enriched in known T2D-associated loci. Notably, allelic imbalance in paternally expressed gene 3 (PEG3) was associated with its promoter methylation and T2D status. Finally, RNA editing events were less common in islets than previously suggested in other tissues. Taken together, this study provides new insights into the complexity of gene regulation in human pancreatic islets and better understanding of how genetic variation can influence glucose metabolism.T ype 2 diabetes (T2D) is an increasing global health problem (1). Although genome-wide association studies (GWAS) have yielded more than 70 loci associated with T2D or related traits (2, 3), they have not provided the expected breakthrough in our understanding of the pathogenesis of the disease. They have nonetheless pointed at a central role of the pancreatic islets and β-cell dysfunction in the development of the disease (4, 5). It therefore seems pertinent to focus on human pancreatic islets to obtain insights into the molecular mechanisms causing the disease (6, 7). Given that most SNPs associated with T2D lie in noncoding regions, the majority of causal variants are likely to regulate gene expression rather than protein function per se. Therefore, combination of DNA and RNA sequencing in the same individuals may help to disentangle the role these SNPs play in the pathogenesis of the disease (8). Although the human pancreatic islet transcriptome has been previously described (6, 9-18), using microarrays or RNA sequencing of a limited number of nondiabetic individuals, this has not allowed a more global analysis of the complexity of the islet transcriptome in T2D. Here we combined genotypic imputation, expression microarrays, and exome and RNA sequencing (ExomeSeq and RNA-Seq) in a large number of human pancreatic islets from deceased donors with and without T2D. This study identified a number of novel genes, including long intergenic noncoding RNAs (lincRNAs), whose expression and/or splicing influences insulin secretion and is associated with glycemia. In addition, we provide a catalog of RNA editing and allele-specific expr...

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“…However, the use of rodent models as a proxy for human disease comes at the risk of identifying signals that protect mouse but not human beta cells against death. For example, systematic comparison of the transcriptomes of purified mouse and human beta cells revealed that human beta cells, in contrast to mouse beta cells, express very few to no receptors for the related cytokines prolactin, GH or ciliary neurotrophic factor [13,14]. This would suggest that potential protective effects of these factors may not translate to human beta cells.…”

Section: Gfpmentioning

confidence: 97%

“…This would suggest that potential protective effects of these factors may not translate to human beta cells. Similarly, mouse beta cells express very high levels of the type 1 IL-1 receptor message and protein (Il1r1/IL1R1) [13], while the expression of IL1R1 in human islets is markedly lower and enriched in non-beta cells [14], which raises the question of whether human beta cells would show an equally robust response to an insult mediated by a cytokine cocktail that included IL-1β. Of course, in most studies on mouse beta cells [4,13] they are isolated from adults whose age is measured in months; a confounder that is difficult to avoid when using mouse beta cells to model diseases of the adult human islet.…”

Section: Gfpmentioning

confidence: 98%

Tuning to the right signal

Huising

2015

Diabetologia

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Pancreatic beta cells are clustered in islets of Langerhans together with alpha cells in an arrangement that facilitates the tight coordination of insulin and glucagon secretion at the source of their release. Other secretory cells, including somatostatin-secreting delta cells and pancreatic polypeptide cells, co-localise with alpha and beta cells in the islet and serve to modulate islet endocrine output. A multitude of non-secretory cell types, including endothelial cells, pericytes, stromal cells, glial cells and macrophages, complete the cellular make up of the islet, which is further enhanced by (para)sympathetic nerve terminals that impinge on the islets via neurotransmitters released in the islet microenvironment. While this islet architecture is relatively simple compared with the vast complexity of the central nervous system, the constellation of cell types united in the islet nevertheless provides a rich substrate for local paracrine and autocrine interactions that affect diverse aspects of islet physiology, ranging from the modulation of hormone secretion to the regulation of islet cell mass via proliferation and death. In this issue of Diabetologia (DOI: 10.1007/s00125-015-3552-5), Yang et al take the notion of rich crosstalk within the islet as their point of departure for a systematic evaluation of the beta cellprotective properties of an extensive panel of over 200 factors, with some surprising and highly interesting results, as discussed in this commentary.

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Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome

Cited by 170 publications

References 43 publications

Function of Isolated Pancreatic Islets From Patients at Onset of Type 1 Diabetes: Insulin Secretion Can Be Restored After Some Days in a Nondiabetogenic Environment In Vitro

Function of Isolated Pancreatic Islets From Patients at Onset of Type 1 Diabetes: Insulin Secretion Can Be Restored After Some Days in a Nondiabetogenic Environment In Vitro

Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism

Tuning to the right signal

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