Pancreatic islet epigenomics reveals enhancer clusters that are enriched in Type 2 diabetes risk variants
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ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR348807.fastq.gz | Fastqsanger.gz | |||
| ERR348808.fastq.gz | Fastqsanger.gz | |||
| ERR348809.fastq.gz | Fastqsanger.gz | |||
| ERR348810.fastq.gz | Fastqsanger.gz | |||
| ERR348811.fastq.gz | Fastqsanger.gz |
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Project description:We combined ChIP-seq of chromatin marks and key islet transcription factor with RNA-seq in human islets to map cis-regulatory networks in this primary tissue. The output of this project provides a reference map to dissect genetic variants that alter the susceptibility for Type 2 diabetes, and assist efforts to generate new beta-cells by transcriptional programming strategies
2014-01-01 | E-MTAB-1919 | biostudies-arrayexpress
Project description:Type 2 diabetes affects over 300 million people, causing severe complications and premature death, yet the underlying molecular mechanisms are largely unknown. Pancreatic islet dysfunction is central in type 2 diabetes pathogenesis, and understanding islet genome regulation could therefore provide valuable mechanistic insights. We have now mapped and examined the function of human islet cis-regulatory networks. We identify genomic sequences that are targeted by islet transcription factors to drive islet-specific gene activity and show that most such sequences reside in clusters of enhancers that form physical three-dimensional chromatin domains. We find that sequence variants associated with type 2 diabetes and fasting glycemia are enriched in these clustered islet enhancers and identify trait-associated variants that disrupt DNA binding and islet enhancer activity. Our studies illustrate how islet transcription factors interact functionally with the epigenome and provide systematic evidence that the dysregulation of islet enhancers is relevant to the mechanisms underlying type 2 diabetes.
| S-EPMC3935450 | biostudies-literature
Project description:Type 1 diabetes is an autoimmune destruction of pancreatic islet beta cell disease, and it is important to find new alternative source of the islet beta cells to replace the damaged cells. Human embryonic stem (hES) cells possess unlimited self-renewal and pluripotency and thus have the potential to provide an unlimited supply of different cell types for tissue replacement. The hES-T3 cells with normal female karyotype were first differentiated into embryoid bodies and then induced to generate the pancreatic islet-like cell clusters, which expressed pancreatic islet cell-specific markers of insulin, glucagon and somatostatin. The expression profiles of microRNAs and mRNAs from the pancreatic islet-like cell clusters were further analyzed and compared with those of undifferentiated hES-T3 cells and differentiated embryoid bodies. MicroRNAs negatively regulate the expression of protein-coding mRNAs. The pancreatic islet-like cell clusters were found to exhibit very high expression of microRNAs miR-186, miR-199a and miR-339, which down-regulated the expression of LIN28, PRDM1, CALB1, GCNT2, RBM47, PLEKHH1, RBPMS2 and PAK6. Therefore, these microRNAs are very likely to play important regulatory roles in the differentiation of pancreatic islet cells and early embryonic development. In this investigation, both miRNA and mRNA expression profiles from the pancreatic islet-like cell clusters differentiated from hES-T3 cells (T3pi) were quantitatively determined and compared with those of undifferentiated hES-T3 cells grown on mouse embryonic fibroblast (MEF) feeder (T3ES) and embryoid bodies differentiated from hES-T3 cells (T3EB). Several target genes of pancreatic islet cell-specific miRNAs were identified. ***This submission represents the mRNA expression component of the study only***
2010-09-29 | E-GEOD-14503 | biostudies-arrayexpress
Project description:Type 1 diabetes is an autoimmune destruction of pancreatic islet beta cell disease, and it is important to find new alternative source of the islet beta cells to replace the damaged cells. Human embryonic stem (hES) cells possess unlimited self-renewal and pluripotency and thus have the potential to provide an unlimited supply of different cell types for tissue replacement. The hES-T3 cells with normal female karyotype were first differentiated into embryoid bodies and then induced to generate the pancreatic islet-like cell clusters, which expressed pancreatic islet cell-specific markers of insulin, glucagon and somatostatin. The expression profiles of microRNAs and mRNAs from the pancreatic islet-like cell clusters were further analyzed and compared with those of undifferentiated hES-T3 cells and differentiated embryoid bodies. MicroRNAs negatively regulate the expression of protein-coding mRNAs. The pancreatic islet-like cell clusters were found to exhibit very high expression of microRNAs miR-186, miR-199a and miR-339, which down-regulated the expression of LIN28, PRDM1, CALB1, GCNT2, RBM47, PLEKHH1, RBPMS2 and PAK6. Therefore, these microRNAs are very likely to play important regulatory roles in the differentiation of pancreatic islet cells and early embryonic development.
2010-09-30 | GSE14503 | GEO
Project description:Identification of transcriptional profile of several genes involved in diabetes in islet-derived extracellular vesicles (Evs). Recently, EVs are identified as a new mechanism in cell-to-cell communication by transfer of protein and genic information (mRNA, microRNA). Their role is under investigation in immunology, stem cell and cancer, but not in islets and diabetes. The aim of this experiment is to identify mRNA transcripts (in particular, mRNA transcripts involved in diabetes pathophysiology) present in islet Evs.
2012-08-02 | E-MEXP-3695 | biostudies-arrayexpress
Project description:Genes involved in distinct diabetes types suggest shared disease mechanisms. We show that rare ONECUT1 coding variants cause monogenic recessive diabetes (neonatal or very early-onset, syndromic) in two unrelated patients, and monogenic dominant diabetes (early adult-onset) in heterozygous relatives of these and 13 additional unrelated cases. Patients heterozygous for rare ONECUT1 coding variants define a subgroup of T2D with early-onset diabetes and other features. In addition, common regulatory ONECUT1 variants are associated with multifactorial T2D. Directed differentiation of human pluripotent stem cells to the pancreatic lineage revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. We uncovered that ONECUT1 activates the pro-endocrine genes NKX6.1 and NKX2.2 through binding to their cis-regulatory elements. Globally, ONECUT1-directed gene transcription occurs in association with major islet transcription factors, at clusters of pancreas- and endocrine-specific enhancers within open chromatin. ONECUT1 regulates a transcriptional and epigenetic machinery critical for proper endocrine pancreatic development, involved in a spectrum of diabetes, monogenic recessive and dominant, and multifactorial.
2021-11-03 | PXD018887 | Pride
Project description:Dysregulation of glucagon secretion in type 1 diabetes (T1D) involves hypersecretion during postprandial states, but insufficient secretion during hypoglycemia. The sympathetic nervous system regulates glucagon secretion. To investigate islet sympathetic innervation in T1D, sympathetic tyrosine hydroxylase (TH) axons were analyzed in control non-diabetic organ donors, non-diabetic islet autoantibody-positive individuals (AAb), and age-matched persons with T1D. Islet TH axon numbers and density were significantly decreased in AAb compared to T1D with no significant differences observed in exocrine TH axon volume or lengths between groups. TH axons were in close approximation to islet α-cells in T1D individuals with long-standing diabetes. Islet RNA-sequencing and qRT-PCR analyses identified significant alterations in noradrenalin degradation, α-adrenergic signaling, cardiac b-adrenergic signaling, catecholamine biosynthesis, and additional neuropathology pathways. The close approximation of TH axons at islet α-cells supports a model for sympathetic efferent neurons directly regulating glucagon secretion. Sympathetic islet innervation and intrinsic adrenergic signaling pathways could be novel targets for improving glucagon secretion in T1D.
2021-08-09 | GSE181674 | GEO
Project description:Single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq) creates new opportunities to dissect cell type-specific mechanisms of complex diseases. Since pancreatic islets are central to type 2 diabetes (T2D), we profiled 15,298 islet cells by using combinatorial barcoding snATAC-seq and identified 12 clusters, including multiple alpha, beta and delta cell states. We cataloged 228,873 accessible chromatin sites and identified transcription factors underlying lineage- and state-specific regulation. We observed state-specific enrichment of fasting glucose and T2D genome-wide association studies for beta cells and enrichment for other endocrine cell types. At T2D signals localized to islet-accessible chromatin, we prioritized variants with predicted regulatory function and co-accessibility with target genes. A causal T2D variant rs231361 at the KCNQ1 locus had predicted effects on a beta cell enhancer co-accessible with INS and genome editing in embryonic stem cell-derived beta cells affected INS levels. Together our findings demonstrate the power of single-cell epigenomics for interpreting complex disease genetics.
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Project description:Type 1 diabetes (T1D) usually has a preclinical phase identified by the presence of circulating autoantibodies to pancreatic islet antigens, and most young children who have multiple autoantibodies progress to diabetes within 10 years. While autoantibodies denote underlying islet autoimmunity, how this process is initiated and then progresses to clinical diabetes on a background of genetic susceptibility is not clearly understood. We analysed gene expression by RNA-seq in four types of immune cells from five genetically at-risk children with islet autoantibodies who progressed to diabetes in ≤ 3 years (‘progressors’) and in five at-risk children matched for sex, age and HLA who had not progressed to diabetes (‘non-progressors’).
2022-03-09 | GSE185190 | GEO
Project description:Single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq) creates new opportunities to dissect cell type-specific mechanisms of complex diseases. Since pancreatic islets are central to type 2 diabetes (T2D), we profiled 15,298 islet cells by using combinatorial barcoding snATAC-seq and identified 12 clusters, including multiple alpha, beta and delta cell states. We cataloged 228,873 accessible chromatin sites and identified transcription factors underlying lineage- and state-specific regulation. We observed state-specific enrichment of fasting glucose and T2D genome-wide association studies for beta cells and enrichment for other endocrine cell types. At T2D signals localized to islet-accessible chromatin, we prioritized variants with predicted regulatory function and co-accessibility with target genes. A causal T2D variant rs231361 at the KCNQ1 locus had predicted effects on a beta cell enhancer co-accessible with INS and genome editing in embryonic stem cell-derived beta cells affected INS levels. Together our findings demonstrate the power of single-cell epigenomics for interpreting complex disease genetics.
2021-01-14 | GSE163610 | GEO