79-OR: Signal-Dependent Chromatin Accessibility Dynamics in Pancreatic Islet Dysfunction

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 79-OR
Author(s):  
ZONG WEI
Keyword(s):  
Pancreatic Islet ◽  
Chromatin Accessibility ◽  
Islet Dysfunction

scholarly journals Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Matthias Thurner ◽  
Martijn van de Bunt ◽  
Jason M Torres ◽  
Anubha Mahajan ◽  
Vibe Nylander ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islet ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Human Islets ◽  
Chromatin Accessibility ◽  
Chromatin State ◽  
Open Chromatin ◽  
Genome Wide Association Studies

Human genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n = 17) and DNA methylation (whole-genome bisulphite sequencing, n = 10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including CDC123, ADCY5, KLHDC5) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis.

scholarly journals Pancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
William W. Greenwald ◽  
Joshua Chiou ◽  
Jian Yan ◽  
Yunjiang Qiu ◽  
Ning Dai ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islet ◽  
Chromatin Accessibility ◽  
Diabetes Risk ◽  
Distal Enhancer

scholarly journals Loss of ARNT/HIF1β Mediates Altered Gene Expression and Pancreatic-Islet Dysfunction in Human Type 2 Diabetes

Cell ◽  
2005 ◽  
Vol 122 (3) ◽  
pp. 337-349 ◽  
Author(s):  
Jenny E. Gunton ◽  
Rohit N. Kulkarni ◽  
SunHee Yim ◽  
Terumasa Okada ◽  
Wayne J. Hawthorne ◽  
...  
Keyword(s):  
Gene Expression ◽  
Type 2 Diabetes ◽  
Pancreatic Islet ◽  
Altered Gene Expression ◽  
Human Type ◽  
Islet Dysfunction ◽  
Altered Gene

scholarly journals Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci

2017 ◽  
Author(s):  
Matthias Thurner ◽  
Martijn van de Bunt ◽  
Jason M Torres ◽  
Anubha Mahajan ◽  
Vibe Nylander ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Pancreatic Islet ◽  
Molecular Mechanisms ◽  
Association Studies ◽  
Human Islets ◽  
Chromatin Accessibility ◽  
Chromatin State ◽  
Open Chromatin ◽  
Genome Wide Association Studies

AbstractHuman genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n=17) and DNA methylation (whole-genome bisulphite sequencing, n=10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including CDC123, ADCY5, KLHDC5) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis.

Mitochondria Play a Key Role in Oxidative Stress-induced Pancreatic Islet Dysfunction after Severe Burns

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Xinzhu Liu ◽  
Zhaoxing Liu ◽  
Dawei Li ◽  
Yuezeng Niu ◽  
Wen Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pancreatic Islet ◽  
Severe Burns ◽  
Islet Dysfunction

Loss of β-arrestin2 mediates pancreatic-islet dysfunction in mice

2013 ◽  
Vol 435 (3) ◽  
pp. 345-349 ◽  
Author(s):  
Mingliang Zhang ◽  
Yunxia Zhu ◽  
Kaida Mu ◽  
Ling Li ◽  
Junxi Lu ◽  
...  
Keyword(s):  
Pancreatic Islet ◽  
Islet Dysfunction

scholarly journals Chromatin accessibility variations across pancreatic islet maturation

2019 ◽  
Author(s):  
Jonathan Sobel ◽  
Claudiane Guay ◽  
Adriana Rodriguez-Trejo ◽  
Lisa Stoll ◽  
Véronique Menoud ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Islet ◽  
Regulatory Networks ◽  
Neonatal Period ◽  
Expression Profiles ◽  
Cell Mass ◽  
Chromatin Accessibility ◽  
Cellular Reprogramming ◽  
Open Chromatin ◽  
Adult Rat

Glucose-induced insulin secretion, a peculiar property of fully mature β-cells, is only achieved after birth and is preceded by a phase of intense proliferation. These events occurring in the neonatal period are decisive for the establishment of an appropriate functional β-cell mass that provides the required insulin throughout life. However, key regulators of gene expression involved in cellular reprogramming along pancreatic islet maturation remain to be elucidated. The present study addressed this issue by mapping open chromatin regions in newborn versus adult rat islets using the ATAC-seq assay. Accessible regions were then correlated with the expression profiles of mRNAs to unveil the regulatory networks governing functional islet maturation. This led to the identification of Scrt1, a novel transcriptional repressor controlling β-cell proliferation.

scholarly journals Dissecting mechanisms of human islet differentiation and maturation through epigenome profiling

2019 ◽  
Author(s):  
Juan R. Alvarez-Dominguez ◽  
Julie Donaghey ◽  
Jennifer H. R. Kenty ◽  
Niloofar Rasouli ◽  
Aharon Helman ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Pancreatic Islet ◽  
Islet Cell ◽  
Islet Cells ◽  
Chromatin Accessibility ◽  
Human Islet ◽  
Human Stem Cells ◽  
Insulin Synthesis

SUMMARYInvestigating pancreatic islet differentiation from human stem cells in vitro provides a unique opportunity to dissect mechanisms that operate during human development in utero. We developed methods to profile DNA methylation, chromatin accessibility, and histone modifications from pluripotent stem cells to mature pancreatic islet cells, uncovering widespread epigenome remodeling upon endocrine commitment. Key lineage-defining loci are epigenetically primed before activation, foreshadowing cell fate commitment, and we show that priming of α-cell-specific enhancers steers polyhormonal cells toward an α-cell fate. We further dissect pioneer factors and core regulatory circuits across islet cell differentiation and maturation stages, which identify LMX1B as a key regulator of in vitro-derived endocrine progenitors. Finally, by contrasting maturing stem cell-derived to natural β-cells, we discover that circadian metabolic cycles trigger rhythmic control of insulin synthesis and release and promote mature insulin responsiveness via an increased glucose threshold. These findings form a basis for understanding mechanisms orchestrating human islet cell specification and maturation.

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