Single-cell chromatin landscapes of human islets in normoglycemia, prediabetes and type 2 diabetes
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE169453 | GEO | 2023/02/07
REPOSITORIES: GEO
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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.
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Project description:We have studied the impact of T2D on open chromatin in human pancreatic islets. We used assay for transposase-accessible chromatin using sequencing (ATAC-seq) to profile open chromatin in islets from T2D and non-diabetic donors. We identified ATAC-seq peaks representing open chromatin regions in islets of non-diabetic and diabetic donors. The majority of ATAC-seq peaks mapped near transcription start sites. Additionally, peaks were enriched in enhancer regions and in regions where islet-specific TFs bind. Islet ATAC-seq peaks overlap with SNPs associated with T2D and with additional SNPs in LD with known T2D SNPs. There was enrichment of open chromatin regions near highly expressed genes in human islets.
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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.
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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.
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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.
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Project description:Glucocorticoids are key regulators of glucose homeostasis and pancreatic islet function. In this study we used ATAC-seq and RNA-seq to map chromatin accessibility and gene expression from eleven primary human islet samples cultured in vitro with the glucocorticoid dexamethasone at multiple doses and durations. We identified thousands of accessible chromatin sites and genes with significant changes in activity in response to glucocorticoids. Chromatin sites up-regulated in glucocorticoid signaling were prominently enriched for glucocorticoid receptor binding sites and up-regulated genes were enriched for ion transport and lipid metabolism, whereas down-regulated chromatin sites and genes were enriched for inflammatory, stress response and proliferative processes. Genetic variants associated with glucose levels and T2D risk were enriched in glucocorticoid-responsive chromatin sites, including fine-mapped variants at 51 known signals. Among fine-mapped variants in glucocorticoid-responsive chromatin, a likely casual variant at the 2p21 locus had glucocorticoid-dependent allelic effects on beta cell enhancer activity and affected SIX2 and SIX3 expression. Our results provide a comprehensive map of islet regulatory programs in response to glucocorticoids through which we uncover a role for islet glucocorticoid signaling in mediating genetic risk of T2D.
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Project description:In this study, we achieved integrated transcriptomic and proteomic profiles of GK islets in a time-course fashion at different stages of T2D. Subsequent bioinformatics analysis revealed the chronological order of T2D-related molecular events during the deterioration of pancreatic islets. Our large quantitative dataset provide a valuable resource to obtain a comprehensive picture of the mechanisms responsible for islet dysfunction and to identify potential interventions to prevent beta-cell failure in human T2D.
2017-06-02 | PXD004709 | Pride
Project description:Recent advances in the understanding of the genetics of type 2 diabetes (T2D) susceptibility have focused attention on the regulation of transcriptional activity within the pancreatic beta-cell. MicroRNAs (miRNAs) represent an important component of regulatory control, and have proven roles in the development of human disease and control of glucose homeostasis. We set out to establish the miRNA profile of human pancreatic islets and of enriched beta-cell populations, and to explore their potential involvement in T2D susceptibility. We used Illumina small RNA sequencing to profile the miRNA fraction in three preparations each of primary human islets and of enriched beta-cells generated by fluorescence-activated cell sorting. In total, 366 miRNAs were found to be expressed (i.e. >100 cumulative reads) in islets and 346 in beta-cells; of the total of 384 unique miRNAs, 328 were shared. A comparison of the islet-cell miRNA profile with those of 15 other human tissues identified 40 miRNAs predominantly expressed (i.e. >50% of all reads seen across the tissues) in islets. Several highly-expressed islet miRNAs, such as miR-375, have established roles in the regulation of islet function, but others (e.g. miR-27b-3p, miR-192-5p) have not previously been described in the context of islet biology. As a first step towards exploring the role of islet-expressed miRNAs and their predicted mRNA targets in T2D pathogenesis, we looked at published T2D association signals across these sites. We found evidence that predicted mRNA targets of islet-expressed miRNAs were globally enriched for signals of T2D association (p-values <0.01, q-values <0.1). At six loci with genome-wide evidence for T2D association (AP3S2, KCNK16, NOTCH2, SCL30A8, VPS26A, and WFS1) predicted mRNA target sites for islet-expressed miRNAs overlapped potentially causal variants. In conclusion, we have described the miRNA profile of human islets and beta-cells and provide evidence linking islet miRNAs to T2D pathogenesis. Examination of the miRNA profiles in 3 preparations of isolated pancreatic islets and 3 preparations of FACS-enriched pancreatic beta-cells
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