ATAC-seq on human pancreatic islets
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE129383 | GEO | 2019/04/06
REPOSITORIES: GEO
Similar Datasets
Project description:We used single cell multiome (ATAC and RNA) sequencing to profile 85266 islet cells from 20 individuals, including islets from non-diabetic, pre-diabetic and type 2 diabetic (T2D) donors. We characterize changes in regulatory programs of islet cell types and subtypes in T2D progression, describe the relationship of these programs to genetic risk for T2D, and use allelic imbalance mapping to define cell type-specific functions for candidate T2D causal variants.
2023-02-07 | GSE200044 | GEO
Project description:In this study, we used single cell nucleus ATAC-seq (snATAC-seq) to profile 218,973 islet cells from 34 individuals, including islets from non-diabetic, pre-diabetic and type 2 diectic (T2D) donors. We characterize changes in regulatory programs of islet cell types in T2D progression, describe the relationship of these programs to genetic risk for T2D, and use allelic imbalance mapping to define cell type-specific functions for candidate T2D causal variants.
2023-02-07 | GSE169453 | GEO
Project description:Close to 50 genetic loci have been associated with type 2 diabetes (T2D), but they explain only 15% of the heritability. In an attempt to identify additional T2D genes, we analyzed global gene expression in human islets from 63 donors. Islets from cadaver donors (54 non-diabetic and 9 diabetic) were provided by the Nordic Islet Transplantation Programme (www.nordicislets.org), Uppsala University. The microarrays were performed using GeneChipM-BM-. Human Gene 1.0 ST whole transcript according to Affymetrix standard protocol.
2012-07-05 | E-GEOD-38642 | biostudies-arrayexpress
Project description:Objective: Although glucagon-secreting α-cells and insulin-secreting β-cells have opposing functions in regulating plasma glucose levels, the two cell types share a common developmental origin and have overlaps in their transcriptome and epigenome profiles. Notably, destruction of one of these cell populations can stimulate repopulation via transdifferentiation of the other cell type, at least in mice, suggesting plasticity between these cell fates. Furthermore, dysfunction of both α- and β-cells contributes to the pathophysiology of type 1 and type 2 diabetes, and β-cell de-differentiation has been proposed to contribute to type 2 diabetes. Our objective was to delineate the molecular properties that maintain islet cell type specification yet allow for cellular plasticity. We hypothesized that correlating cell type-specific transcriptomes with an atlas of open chromatin will identify novel genes and transcriptional regulatory elements such as enhancers involved in α- and β-cell specification and plasticity. Methods: We sorted human a- and b-cells and performed the â??Assay for Transposase-Accessible Chromatin with high throughput sequencingâ?? (ATAC-seq) and mRNA-seq, followed by integrative analysis to identify cell type-selective gene regulatory regions. Results: We identified numerous transcripts with either α-cell- or β-cell-selective expression and discovered the cell type-selective open chromatin regions that correlate with these gene activation patterns. We confirmed cell type-selective expression on the protein level for two of the top hits from our screen. The â??group specific proteinâ?? (GC; or vitamin D binding protein) was restricted to a-cells, while CHODL (chondrolectin) immunoreactivity was only present in b-cells. Furthermore, α-cell- and β-cell-selective ATAC-seq peaks were identified to overlap with known binding sites for islet transcription factors, as well as with common single nucleotide polymorphisms (SNPs) previously identified as risk loci for type 2 diabetes. Conclusions: We have determined the genetic landscape of human α- and β-cells based on chromatin accessibility and transcript levels, which allowed for detection of novel α- and β-cell signature genes not previously known to be expressed in islets. Using fine-mapping of open chromatin, we have identified thousands of potential cis-regulatory elements that operate in an endocrine cell type-specific fashion. ATAC-seq on 3 human alpha cell samples, 3 human beta cell samples, and 2 human acinar cell samples. RNA-seq on 7 human alpha cell samples and 8 human beta cell samples.
2015-12-23 | E-GEOD-76268 | biostudies-arrayexpress
Project description:Alpha TC1 (αTC1) and Beta-TC-6 (βTC6) mouse islet cell lines are cellular models of islet (dys)function and type 2 diabetes (T2D). However, genomic characteristics of these cells, and their similarities to primary islet alpha and beta cells, are undefined. Here, we report the epigenomic (ATAC-seq) and transcriptomic (RNA-seq) landscapes of αTC1 and βTC6 cells. Each cell type exhibits hallmarks of its primary islet cell counterpart including cell-specific expression of beta (e.g., Pdx1) and alpha (e.g., Arx) cell transcription factors (TFs), and enrichment of binding motifs for these TFs in αTC1/βTC6 cis-regulatory elements. αTC1/βTC6 transcriptomes overlap significantly with the transcriptomes of primary mouse/human alpha and beta cells. Our data further indicate that ATAC-seq detects cell-specific regulatory elements for cell types comprising ≥ 20% of a mixed cell population. We identified αTC1/βTC6 cis-regulatory elements orthologous to those containing type 2 diabetes (T2D)-associated SNPs in human islets for 33 loci, suggesting these cells’ utility to dissect T2D molecular genetics in these regions. Together, these maps provide important insights into the conserved regulatory architecture between αTC1/βTC6 and primary islet cells that can be leveraged in functional (epi)genomic approaches to dissect the genetic and molecular factors controlling islet cell identity and function.
2017-09-20 | GSE99954 | GEO
Project description:Identifying cis-regulatory elements is important to understand how human pancreatic islets modulate gene expression in physiologic or pathophysiologic (e.g., diabetic) conditions. We conducted genome-wide analysis of DNase I hypersensitive sites, histone H3 lysine methylation marks (K4me1, K4me3, K79me2), and CCCTC factor (CTCF) binding in human islets. This identified ~18,000 putative promoters (several hundred novel and islet-active). Surprisingly, active promoter marks were absent at genes encoding islet-specific hormones, suggesting a distinct regulatory mechanism. Of 34,039 distal (non-promoter) regulatory elements, 47% are islet-unique and 22% are CTCF-bound. These findings present a global snapshot of the human islet epigenome and should provide functional context for non-coding variants emerging from genetic studies of T2D and other pancreatic islet disorders. Three different islet samples were tested for DNase I hypersensitivity by DNase-Seq. Five different primary pancreatic islet samples were evaluated for several chromatin modifications (H3K4me3, H3K4me1, H3K79me2) by ChIP-seq. One islet sample was evaluated for CTCF binding via ChIP-seq, All ChIP-seq samples have both non-specific IP (GFP) and input DNA controls.
2010-11-02 | E-GEOD-23784 | biostudies-arrayexpress
Project description:Pancreatic islet (dys)function is central to glucose homeostasis and type 2 diabetes (patho)physiology. Human islets consist of multiple endocrine (alpha, beta, delta, gamma), endothelial, and resident/inflitrating immune cells whose coordinated functions modulate glucose mobilization or disposal. Single cell transcriptome profiling (scRNA-seq) studies have been applied to dissect human islet cellular heterogeneity, identify islet cell (sub)populations, and define their molecular repertoire. However, precise understanding of cell type-specific alterations in type 2 diabetic vs. non-diabetic individuals is lacking, due in part to the limited number of individuals or single cell transcriptomes per individual profiled for comparison. Here, we create a comprehensive single cell transcriptome atlas of 245,878 human islet cells from 48 individuals spanning non-diabetic (ND), pre-diabetic (PD), and type 2 diabetic (T2D) states and matched for sex, age, and ancestry and define marker gene sets that are robustly expressed across disease states for each of the 14 cell types identified. We observe significant decreases in the number of beta cells sampled from T2D vs. ND or PD donors. Two of eight putative beta cell subpopulations, with ‘high functioning’ and ‘senescent’ cell gene signatures, increase and decrease in T2D donor islets, respectively. Importantly, we identify 511 differentially expressed genes in beta cells from T2D vs. ND donors. This includes monogenic and type 2 diabetes effector genes, such as HNF1A, DGKB, ST6GAL1, and FXYD2, for which genetic and environmental effects on their expression is concordant. Human beta cell and islet knockdown of selected newly-identified down-regulated genes impairs beta cell viability or function. Together, this study provides new and robust, cell type-resolved insights on the cellular and molecular changes in healthy vs. diabetic human islets and represents a valuable resource to the islet biology and type 2 diabetes communities.
2023-03-30 | GSE221156 | GEO
Project description:Type 2 diabetes is associated with defective insulin secretion and reduced β-cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making insulin supplementation necessary. Reversibility of b-cell failure is a key translational question. Here, we reverse-engineered and interrogated pancreatic islet-specific regulatory networks to discover T2D-specific subpopulations characterized by metabolic-inflexibility and endocrine-progenitor/stem cell features. Single-cell gain- and loss-of-function and glucose-induced Ca++ flux analyses of top candidate MR in islet cells validated transcription factor BACH2 and associated epigenetic effectors as a key driver of T2D cell states. BACH2 knockout in T2D islets reversed cellular features of the disease, restoring a non-diabetic phenotype. BACH2-immunoreactive islet cells increased ~4-fold in diabetic patients, confirming the algorithmic prediction of clinically relevant subpopulations. Treatment with a BACH inhibitor lowered glycemia and increased plasma insulin levels in diabetic mice, and restored insulin secretion in diabetic mice and human islets. The findings suggest that T2D-specific populations of failing b-cells can be reversed and indicate pathways for pharmacological intervention, including via BACH2 inhibition.
2021-11-11 | GSE137766 | GEO
Project description:Type 2 diabetes is associated with defective insulin secretion and reduced β-cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making insulin supplementation necessary. Reversibility of b-cell failure is a key translational question. Here, we reverse-engineered and interrogated pancreatic islet-specific regulatory networks to discover T2D-specific subpopulations characterized by metabolic-inflexibility and endocrine-progenitor/stem cell features. Single-cell gain- and loss-of-function and glucose-induced Ca++ flux analyses of top candidate MR in islet cells validated transcription factor BACH2 and associated epigenetic effectors as a key driver of T2D cell states. BACH2 knockout in T2D islets reversed cellular features of the disease, restoring a non-diabetic phenotype. BACH2-immunoreactive islet cells increased ~4-fold in diabetic patients, confirming the algorithmic prediction of clinically relevant subpopulations. Treatment with a BACH inhibitor lowered glycemia and increased plasma insulin levels in diabetic mice, and restored insulin secretion in diabetic mice and human islets. The findings suggest that T2D-specific populations of failing b-cells can be reversed and indicate pathways for pharmacological intervention, including via BACH2 inhibition.
2021-11-11 | GSE136887 | GEO
Project description:Type 2 diabetes is associated with defective insulin secretion and reduced β-cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making insulin supplementation necessary. Reversibility of b-cell failure is a key translational question. Here, we reverse-engineered and interrogated pancreatic islet-specific regulatory networks to discover T2D-specific subpopulations characterized by metabolic-inflexibility and endocrine-progenitor/stem cell features. Single-cell gain- and loss-of-function and glucose-induced Ca++ flux analyses of top candidate MR in islet cells validated transcription factor BACH2 and associated epigenetic effectors as a key driver of T2D cell states. BACH2 knockout in T2D islets reversed cellular features of the disease, restoring a non-diabetic phenotype. BACH2-immunoreactive islet cells increased ~4-fold in diabetic patients, confirming the algorithmic prediction of clinically relevant subpopulations. Treatment with a BACH inhibitor lowered glycemia and increased plasma insulin levels in diabetic mice, and restored insulin secretion in diabetic mice and human islets. The findings suggest that T2D-specific populations of failing b-cells can be reversed and indicate pathways for pharmacological intervention, including via BACH2 inhibition.
2021-11-11 | GSE98887 | GEO