Interpreting type 1 diabetes risk with genetics and single-cell epigenomics

Chiou, Joshua; Geusz, Ryan J; Okino, Mei-Lin; Han, Jee Yun; Miller, Michael; Melton, Rebecca; Beebe, Elisha; Benaglio, Paola; Huang, Serina; Korgaonkar, Katha; Heller, Sandra; Kleger, Alexander; Preißl, Sebastian; Gorkin, David U.; Sander, Maike; Gaulton, Kyle J.

doi:10.1038/s41586-021-03552-w

Cited by 263 publications

(275 citation statements)

References 108 publications

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“…New analysis tools such as CellPhoneDB give the ability to map interactions between subsets of cells, based on DEG in scRNAseq datasets, which would allow identification of novel interactions between immune cells and beta cells in the pancreas (85,86). This may become increasingly important as we begin to understand the role of beta cell stress and signalling in type 1 diabetes (6) as well as the involvement of other pancreatic cells in diabetes development (23). CellPhoneDB has been used to identify crosstalk between T cells and epithelial cells in ulcerative colitis (87) whilst in rheumatoid arthritis scRNAseq has revealed interaction pathways between B cells, fibroblasts and monocytes (88).…”

Section: Future Perspectives On Scrnaseq In Type 1 Diabetes New Single Cell Methods and Analysis Toolsmentioning

confidence: 99%

“…Recently, Chiou et al combined scATACseq with bulk ATACseq and scRNAseq approaches to link cis-regulatory elements (CREs e.g. gene promoters and enhancers) in peripheral blood cells and pancreatic cells with GWAS of diabetes risk (23). As would be expected this identified many CREs used in T cells and beta cells that had genetic variants associated with T1D susceptibility.…”

Section: Using Scrnaseq To Identify Biomarkers For Progression To Type 1 Diabetes and Phenotypes In T1dmentioning

confidence: 99%

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Insights From Single Cell RNA Sequencing Into the Immunology of Type 1 Diabetes- Cell Phenotypes and Antigen Specificity

et al. 2021

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In the past few years, huge advances have been made in techniques to analyse cells at an individual level using RNA sequencing, and many of these have precipitated exciting discoveries in the immunology of type 1 diabetes (T1D). This review will cover the first papers to use scRNAseq to characterise human lymphocyte phenotypes in T1D in the peripheral blood, pancreatic lymph nodes and islets. These have revealed specific genes such as IL-32 that are differentially expressed in islet –specific T cells in T1D. scRNAseq has also revealed wider gene expression patterns that are involved in T1D and can predict its development even predating autoantibody production. Single cell sequencing of TCRs has revealed V genes and CDR3 motifs that are commonly used to target islet autoantigens, although truly public TCRs remain elusive. Little is known about BCR repertoires in T1D, but scRNAseq approaches have revealed that insulin binding BCRs commonly use specific J genes, share motifs between donors and frequently demonstrate poly-reactivity. This review will also summarise new developments in scRNAseq technology, the insights they have given into other diseases and how they could be leveraged to advance research in the type 1 diabetes field to identify novel biomarkers and targets for immunotherapy.

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Section: Future Perspectives On Scrnaseq In Type 1 Diabetes New Single Cell Methods and Analysis Toolsmentioning

confidence: 99%

Section: Using Scrnaseq To Identify Biomarkers For Progression To Type 1 Diabetes and Phenotypes In T1dmentioning

confidence: 99%

Insights From Single Cell RNA Sequencing Into the Immunology of Type 1 Diabetes- Cell Phenotypes and Antigen Specificity

et al. 2021

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“…T1D is a complex disease caused by autoimmune destruction of β cells. The strong genetic component of T1D [ 241 ] has been surveyed by GWAS [ 242 , 243 , 244 , 245 ]. The HLA region represents approximately half of the familial aggregation of T1D [ 246 ].…”

Section: Genetic Basis Of β Cell Dysfunctionmentioning

confidence: 99%

Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction

Bartolomé

2022

IJMS

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Pancreatic β cell dysfunction is a central component of diabetes progression. During the last decades, the genetic basis of several monogenic forms of diabetes has been recognized. Genome-wide association studies (GWAS) have also facilitated the identification of common genetic variants associated with an increased risk of diabetes. These studies highlight the importance of impaired β cell function in all forms of diabetes. However, how most of these risk variants confer disease risk, remains unanswered. Understanding the specific contribution of genetic variants and the precise role of their molecular effectors is the next step toward developing treatments that target β cell dysfunction in the era of personalized medicine. Protocols that allow derivation of β cells from pluripotent stem cells, represent a powerful research tool that allows modeling of human development and versatile experimental designs that can be used to shed some light on diabetes pathophysiology. This article reviews different models to study the genetic basis of β cell dysfunction, focusing on the recent advances made possible by stem cell applications in the field of diabetes research.

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“…From a clinical standpoint, CFRD and T1D share common features: onset is mostly in young patients, the diagnosis is typically not associated with obesity and insulin therapy is very frequently the therapeutic option. Of interest, a CFTR variant has recently been linked to T1D susceptibility suggesting a further association between CFRD and T1D pathologies (33).…”

Section: Comparison Of Cfrd To Other Forms Of Diabetesmentioning

confidence: 99%

The Potential Causes of Cystic Fibrosis-Related Diabetes

et al. 2021

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Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity, affecting more than 50% of adult CF patients. Despite this high prevalence, the etiology of CFRD remains incompletely understood. Studies in young CF children show pancreatic islet disorganization, abnormal glucose tolerance, and delayed first-phase insulin secretion suggesting that islet dysfunction is an early feature of CF. Since insulin-producing pancreatic β-cells express very low levels of CFTR, CFRD likely results from β-cell extrinsic factors. In the vicinity of β-cells, CFTR is expressed in both the exocrine pancreas and the immune system. In the exocrine pancreas, CFTR mutations lead to the obstruction of the pancreatic ductal canal, inflammation, and immune cell infiltration, ultimately causing the destruction of the exocrine pancreas and remodeling of islets. Both inflammation and ductal cells have a direct effect on insulin secretion and could participate in CFRD development. CFTR mutations are also associated with inflammatory responses and excessive cytokine production by various immune cells, which infiltrate the pancreas and exert a negative impact on insulin secretion, causing dysregulation of glucose homeostasis in CF adults. In addition, the function of macrophages in shaping pancreatic islet development may be impaired by CFTR mutations, further contributing to the pancreatic islet structural defects as well as impaired first-phase insulin secretion observed in very young children. This review discusses the different factors that may contribute to CFRD.

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Interpreting type 1 diabetes risk with genetics and single-cell epigenomics

Cited by 263 publications

References 108 publications

Insights From Single Cell RNA Sequencing Into the Immunology of Type 1 Diabetes- Cell Phenotypes and Antigen Specificity

Insights From Single Cell RNA Sequencing Into the Immunology of Type 1 Diabetes- Cell Phenotypes and Antigen Specificity

Stem Cell-Derived β Cells: A Versatile Research Platform to Interrogate the Genetic Basis of β Cell Dysfunction

The Potential Causes of Cystic Fibrosis-Related Diabetes

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