Epigenomic plasticity enables human pancreatic α to β cell reprogramming
Nuria C. Bramswig,Logan J. Everett,Jonathan Schug,Craig Dorrell,Chengyang Liu,Yanping Luo,Philip R. Streeter,Ali Naji,Markus Grompe,Klaus H. Kaestner +9 more
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TLDR
M mammalian pancreatic islet cells display cell-type-specific epigenomic plasticity, suggesting that epigenomic manipulation could provide a path to cell reprogramming and novel cell replacement-based therapies for diabetes.Abstract:
Insulin-secreting β cells and glucagon-secreting α cells maintain physiological blood glucose levels, and their malfunction drives diabetes development. Using ChIP sequencing and RNA sequencing analysis, we determined the epigenetic and transcriptional landscape of human pancreatic α, β, and exocrine cells. We found that, compared with exocrine and β cells, differentiated α cells exhibited many more genes bivalently marked by the activating H3K4me3 and repressing H3K27me3 histone modifications. This was particularly true for β cell signature genes involved in transcriptional regulation. Remarkably, thousands of these genes were in a monovalent state in β cells, carrying only the activating or repressing mark. Our epigenomic findings suggested that α to β cell reprogramming could be promoted by manipulating the histone methylation signature of human pancreatic islets. Indeed, we show that treatment of cultured pancreatic islets with a histone methyltransferase inhibitor leads to colocalization of both glucagon and insulin and glucagon and insulin promoter factor 1 (PDX1) in human islets and colocalization of both glucagon and insulin in mouse islets. Thus, mammalian pancreatic islet cells display cell-type–specific epigenomic plasticity, suggesting that epigenomic manipulation could provide a path to cell reprogramming and novel cell replacement-based therapies for diabetes.read more
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Single-Cell Transcriptome Profiling of Human Pancreatic Islets in Health and Type 2 Diabetes.
Åsa Segerstolpe,Athanasia Palasantza,Pernilla Eliasson,Eva-Marie Andersson,Anne-Christine Andréasson,Xiaoyan Sun,Simone Picelli,Alan Sabirsh,Maryam Clausen,Magnus K. Bjursell,David M. Smith,Maria Kasper,Carina Ämmälä,Rickard Sandberg,Rickard Sandberg +14 more
TL;DR: Analysis of transcriptomes of thousands of human islet cells from healthy and type 2 diabetic donors demonstrated the utility of the generated single-cell gene expression resource, and revealed subpopulations of α, β, and acinar cells.
Journal ArticleDOI
RNA Sequencing of Single Human Islet Cells Reveals Type 2 Diabetes Genes.
Yurong Xin,Jinrang Kim,Haruka Okamoto,Min Ni,Yi Wei,Christina Adler,Andrew J. Murphy,George D. Yancopoulos,Calvin Lin,Jesper Gromada +9 more
TL;DR: Single-cell RNA sequencing was used to determine the transcriptomes of 1,492 human pancreatic α, β, δ, and PP cells from non-diabetic and type 2 diabetes organ donors and identified cell-type-specific genes and pathways as well as 245 genes with disturbed expression intype 2 diabetes.
Journal ArticleDOI
β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment
Philippe A. Halban,Kenneth S. Polonsky,Donald W. Bowden,Meredith Hawkins,Charlotte Ling,Kieren J. Mather,Alvin C. Powers,Christopher J. Rhodes,Lori Sussel,Gordon C. Weir +9 more
TL;DR: The foundation of β-cell failure in type 2 diabetes (T2D) is examined and areas for future research on the underlying mechanisms that may lead to improved prevention and treatment are suggested.
Journal ArticleDOI
Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion
Tasnim Dayeh,Petr Volkov,Sofia Salö,Elin Hall,Emma Nilsson,Anders H. Olsson,Clare L. Kirkpatrick,Claes B. Wollheim,Lena Eliasson,Tina Rönn,Karl Bacos,Charlotte Ling +11 more
TL;DR: Functional analyses demonstrated that identified candidate genes affect pancreatic β- and α-cells as Exoc3l silencing reduced exocytosis and overexpression of Cdkn1a, Pde7b and Sept9 perturbed insulin and glucagon secretion in clonal α- and β-cells, respectively.
Journal ArticleDOI
Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism
João Fadista,Petter Vikman,Emilia Ottosson Laakso,Inês G. Mollet,Jonathan L.S. Esguerra,Jalal Taneera,Petter Storm,Peter Osmark,Claes Ladenvall,Rashmi B. Prasad,Karin Hansson,Francesca Finotello,K. Uvebrant,Jones K. Ofori,Barbara Di Camillo,Ulrika Krus,Corrado M. Cilio,Ola Hansson,Lena Eliasson,Anders Rosengren,Erik Renström,Claes B. Wollheim,Claes B. Wollheim,Leif Groop +23 more
TL;DR: The data show that the path from genetic variation (SNP) to gene expression is more complex than hitherto often assumed, and that genetic variation can also influence function of a gene by influencing exon usage or splice isoforms (sQTL), allelic imbalance, RNA editing, and expression of noncoding RNAs.
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