scholarly journals Regulatory variants active in iPSC-derived pancreatic progenitor cells are associated with Type 2 Diabetes in adults

2021 ◽  
Author(s):  
Jennifer P. Nguyen ◽  
Agnieszka D'Antonio-Chronowska ◽  
Kyohei Fujita ◽  
Bianca M. Salgado ◽  
Hiroko Matsui ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Chromatin Accessibility ◽  
Cell Type ◽  
Pancreatic Progenitor ◽  
Ductal Cells ◽  
Regulatory Variants ◽  
Pancreatic Progenitor Cells

Pancreatic progenitor cells (PPC) are an early developmental multipotent cell type that give rise to mature endocrine, exocrine, and ductal cells. To investigate the extent to which regulatory variants active in PPC contribute to pancreatic complex traits and disease in the adult, we derived PPC from induced pluripotent stem cells (iPSCs) of nine unrelated individuals and generated single cell profiles of chromatin accessibility (snATAC-seq) and transcriptome (scRNA-seq). While iPSC-PPC differentiation was asynchronous and included cell types from early to late developmental stages, we found that the predominant cell type consisted of NKX6-1+ progenitors. Genetic characterization using snATAC-seq identified 86,261 regulatory variants that either displayed chromatin allelic bias and/or were predicted to affect active transcription factor (TF) binding sites. Integration of these regulatory variants with 380 fine-mapped type 2 diabetes (T2D) risk loci identified regulatory variants in 209 of these loci that are functional in iPSC-PPC, either by affecting transcription factor binding or through association with allelic effects on chromatin accessibility. The PPC active regulatory variants in 65 of these loci showed strong evidence of causally underlying the association with T2D. Our study shows that studying the functional associations of regulatory variation in iPSC-PPC enables the identification and characterization of causal SNPs for adult Type 2 Diabetes.

scholarly journals Pancreatic Progenitor Cells—Recent Studies

Endocrinology ◽  
2008 ◽  
Vol 149 (9) ◽  
pp. 4312-4316 ◽  
Author(s):  
Hsun Teresa Ku
Keyword(s):  
Progenitor Cells ◽  
Cell Biology ◽  
Progenitor Cell ◽  
Cell Activity ◽  
Pancreatic Progenitor ◽  
Ductal Cells ◽  
Multipotent Progenitors ◽  
Pancreatic Progenitor Cells ◽  
Genetic Labeling ◽  
Functional Analyses

Past studies of pancreatic progenitor cell biology relied mostly on histological analyses. Recent studies, using genetic labeling and tracing of progenitors, direct single cell analyses, colony assays, and enrichment of the minor population of progenitor cells through the use of cell surface markers, have strongly suggested that pancreatic progenitor cells with various frequency and lineage potentials, including the multipotent progenitors that give rise to endocrine, exocrine, and duct cells, exist in the developing and adult pancreas. In this review, it is therefore proposed that pancreatic progenitor cells may be organized in a hierarchy, in which the most primitive pan-pancreatic multipotent progenitors are at the top and rare, and the monopotent progenitors are at the bottom and abundant. This model may explain why only drastic injuries lead to effective activation of the progenitor cell compartment of the higher hierarchy, whereas under steady state, pregnancy, and milder injuries, recruitment of preexisting mature cells or their immediate monopotent progenitors could be sufficient to restore metabolic homeostasis. It is also proposed that the morphologically defined ductal cells are likely to be functionally heterogeneous and that endocrine progenitor cell activity should be determined based on functional analyses rather than histological locations.

scholarly journals Identification and functional study of GATA4 gene regulatory variants in type 2 diabetes mellitus

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Liangcai Ding ◽  
Mengdi Cai ◽  
Lu Chen ◽  
Han Yan ◽  
Shicheng Lu ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Transcription Factor ◽  
Complex Disease ◽  
Critical Role ◽  
Functional Study ◽  
Regulatory Variants ◽  
Gene Regulatory

Abstract Background Type 2 diabetes mellitus (T2D) is a common and complex disease. Dysfunction of pancreatic β cells, which cannot release sufficient insulin, plays a central role in T2D. Genetics plays a critical role in T2D etiology. Transcription factor GATA4 is required for the pancreatic development, and GATA4 gene mutations are implicated in neonatal or childhood-onset diabetes. In this study, we aimed to investigate whether regulatory variants in GATA4 gene may change GATA4 levels, conferring susceptibility to T2D development. Methods The promoter region of GATA4 gene was analyzed by targeted sequencing in T2D patients (n = 255) and ethnic-matched controls (n = 371). Dual luciferase activity assay was used for functional study, and EMSA (electrophoretic mobility shift assay) was performed for detecting transcription factor binding. Results Thirteen regulatory variants including 5 SNPs were identified. A novel heterozygous variant (32124C > T) and one SNP [31487C > G (rs1053351749)] were only identified in T2D. Both regulatory variants significantly affected GATA4 gene promoter activity in cultured HEK-293 and INS-1 cells. Furthermore, the variant (32124C > T) evidently enhanced the binding of unknown transcriptional activator. Conclusions Our data suggested that GATA4 gene regulatory variants may contribute to T2D development as a rare risk factor.

scholarly journals Type 2 Diabetes Dysregulates Glucose Metabolism in Cardiac Progenitor Cells

2016 ◽  
Vol 291 (26) ◽  
pp. 13634-13648 ◽  
Author(s):  
Joshua K. Salabei ◽  
Pawel K. Lorkiewicz ◽  
Parul Mehra ◽  
Andrew A. Gibb ◽  
Petra Haberzettl ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Glucose Metabolism ◽  
Progenitor Cells ◽  
Cardiac Progenitor Cells
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