RNA Sequencing of Single Human Islet Cells Reveals Type 2 Diabetes Genes

Xin, Yurong; Kim, Jinrang; Okamoto, Haruka; Ni, Min; Wei, Yi; Adler, Christina; Murphy, Andrew; Yancopouloš, George D.; Lin, Chia‐Hsun; Gromada, Jesper

doi:10.1016/j.cmet.2016.08.018

Cited by 563 publications

(696 citation statements)

References 39 publications

Supporting

Mentioning

629

Contrasting

Order By: Relevance

“…These results suggest that unlike known β-cell associated transcripts, those in α-cells and δ-cells are highly coordinate in their expression pattern among the islets of the DO mice. The β-cell transcripts do not show this same coordinate regulation, suggesting that they may reflect a greater degree of heterogeneity within the β-cell population, as has been previously reported for islets collected from different regions of the pancreas in mice following dietary challenge (ELLENBROEK et al 2013), as well for islets collected from non-diabetic vs. T2D human subjects (DORRELL et al 2016;XIN et al 2016;LAWLOR et al 2017). …”

Section: +mentioning

confidence: 55%

“…The greenyellow module consists of 387 transcripts, including Gcg, Irx1,Irx2,Arx,Mafb,Ttr, Gria3 and Sstr2. These transcripts have been previously associated with selective expression in α-cells (DORRELL et al 2011;ACKERMANN et al 2016;DIGRUCCIO et al 2016;XIN et al 2016;LAWLOR et al 2017). The yellowgreen module contains 109 transcripts, including many that have been linked to selective expression in δ-cells; Sst, Hhex, Rbp4 and Ghsr (DORRELL et al 2011;ACKERMANN et al 2016;DIGRUCCIO et al 2016;XIN et al 2016;LAWLOR et al 2017).…”

Section: Modules Enriched In α-Cell and δ-Cell Specific Transcriptsmentioning

confidence: 93%

See 1 more Smart Citation

Genetic Drivers of Pancreatic Islet Function

et al. 2018

View full text Add to dashboard Cite

The majority of gene loci that have been associated with type 2 diabetes play a role in pancreatic islet function. To evaluate the role of islet gene expression in the etiology of diabetes, we sensitized a genetically diverse mouse population with a Western diet high in fat (45%-kcal) and sucrose (34%) and carried out genome-wide association mapping of diabetes-related phenotypes. We quantified mRNA abundance in the islets and identified 18,820 expression quantitative trait loci. We applied mediation analysis to identify candidate causal driver genes at loci that affect the abundance of numerous transcripts. These include two genes previously associated with monogenic diabetes (PDX1 and HNF4A), as well as three genes with nominal association with diabetes-related traits in humans (FAM83E, IL6ST, and SAT2). We grouped transcripts into gene modules and mapped regulatory loci for modules enriched with transcripts specific for α-cells, and another specific for δ-cells. However, no single module enriched for β-cell-specific transcripts, suggesting heterogeneity of gene expression patterns within the β-cell population. A module enriched in transcripts associated with branched chain amino acid metabolism was the most strongly correlated with physiological traits that reflect insulin resistance. Although the mice in this study were not overtly diabetic, the analysis of pancreatic islet gene expression under dietary-induced stress enabled us to identify correlated variation in groups of genes that are functionally linked to diabetes-associated physiological traits. Our analysis suggests an expected degree of concordance between diabetes-associated loci in the mouse with those found in human populations and demonstrates how the mouse can provide evidence to support nominal associations found in human genome-wide association mapping.4

show abstract

Section: +mentioning

confidence: 55%

Section: Modules Enriched In α-Cell and δ-Cell Specific Transcriptsmentioning

confidence: 93%

Genetic Drivers of Pancreatic Islet Function

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Nonetheless, with the advance of single cell RNA-Seq (Segerstolpe et al, 2016; Wang Y.J. et al, 2016; Xin et al, 2016), we are likely soon to have answers to these questions.…”

Section: Perspectives For Future Studymentioning

confidence: 99%

MiRNAs in β-Cell Development, Identity, and Disease

2017

View full text Add to dashboard Cite

Pancreatic β-cells regulate glucose metabolism by secreting insulin, which in turn stimulates the utilization or storage of the sugar by peripheral tissues. Insulin insufficiency and a prolonged period of insulin resistance are usually the core components of type 2 diabetes (T2D). Although, decreased insulin levels in T2D have long been attributed to a decrease in β-cell function and/or mass, this model has recently been refined with the recognition that a loss of β-cell “identity” and dedifferentiation also contribute to the decline in insulin production. MicroRNAs (miRNAs) are key regulatory molecules that display tissue-specific expression patterns and maintain the differentiated state of somatic cells. During the past few years, great strides have been made in understanding how miRNA circuits impact β-cell identity. Here, we review current knowledge on the role of miRNAs in regulating the acquisition of the β-cell fate during development and in maintaining mature β-cell identity and function during stress situations such as obesity, pregnancy, aging, or diabetes. We also discuss how miRNA function could be harnessed to improve our ability to generate β-cells for replacement therapy for T2D.

show abstract

“…Microarrays and RNA sequencing (RNA-seq) were conducted on endocrine pancreatic cells isolated from human (healthy or diabetic persons) or rodents at adult and embryonic stages [1–9]. More recently, RNA-seq performed on endocrine cell types isolated by FACS or at single-cell level allowed to define the genes enriched in each endocrine cell type in human and mice [7, 10–21]. However, no comprehensive interspecies comparison has been performed so far to define the conserved signatures for each pancreatic cell type, except for two studies comparing human and murine beta cells and reporting some notable differences between these two mammalian species [12, 21].…”

Section: Introductionmentioning

confidence: 99%

Transcriptome analysis of pancreatic cells across distant species highlights novel important regulator genes

et al. 2017

View full text Add to dashboard Cite

BackgroundDefining the transcriptome and the genetic pathways of pancreatic cells is of great interest for elucidating the molecular attributes of pancreas disorders such as diabetes and cancer. As the function of the different pancreatic cell types has been maintained during vertebrate evolution, the comparison of their transcriptomes across distant vertebrate species is a means to pinpoint genes under strong evolutionary constraints due to their crucial function, which have therefore preserved their selective expression in these pancreatic cell types.ResultsIn this study, RNA-sequencing was performed on pancreatic alpha, beta, and delta endocrine cells as well as the acinar and ductal exocrine cells isolated from adult zebrafish transgenic lines. Comparison of these transcriptomes identified many novel markers, including transcription factors and signaling pathway components, specific for each cell type. By performing interspecies comparisons, we identified hundreds of genes with conserved enriched expression in endocrine and exocrine cells among human, mouse, and zebrafish. This list includes many genes known as crucial for pancreatic cell formation or function, but also pinpoints many factors whose pancreatic function is still unknown. A large set of endocrine-enriched genes can already be detected at early developmental stages as revealed by the transcriptomic profiling of embryonic endocrine cells, indicating a potential role in cell differentiation. The actual involvement of conserved endocrine genes in pancreatic cell differentiation was demonstrated in zebrafish for myt1b, whose invalidation leads to a reduction of alpha cells, and for cdx4, selectively expressed in endocrine delta cells and crucial for their specification. Intriguingly, comparison of the endocrine alpha and beta cell subtypes from human, mouse, and zebrafish reveals a much lower conservation of the transcriptomic signatures for these two endocrine cell subtypes compared to the signatures of pan-endocrine and exocrine cells. These data suggest that the identity of the alpha and beta cells relies on a few key factors, corroborating numerous examples of inter-conversion between these two endocrine cell subtypes.ConclusionThis study highlights both evolutionary conserved and species-specific features that will help to unveil universal and fundamental regulatory pathways as well as pathways specific to human and laboratory animal models such as mouse and zebrafish.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-017-0362-x) contains supplementary material, which is available to authorized users.

show abstract

RNA Sequencing of Single Human Islet Cells Reveals Type 2 Diabetes Genes

Cited by 563 publications

References 39 publications

Genetic Drivers of Pancreatic Islet Function

Genetic Drivers of Pancreatic Islet Function

MiRNAs in β-Cell Development, Identity, and Disease

Transcriptome analysis of pancreatic cells across distant species highlights novel important regulator genes

Contact Info

Product

Resources

About