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islet, enhancer, chromatin, data, variants, genes, supplementary, gene, fig, article, signals, loops, risk, enhancers, variant, google, scholar, target, expression, loop, candidate, islets, active, promoter, elements, cas, samples, identified, insulin, atacseq, accessible, signal, eqtl, nature, pancreatic, regulatory, calculated, diabetes, activity, enriched, secretion, human, sample, genetic, hic, sites, reads, enrichment, genomic, locus,

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         headline:Pancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk
         description:Genetic variants affecting pancreatic islet enhancers are central to T2D risk, but the gene targets of islet enhancer activity are largely unknown. We generate a high-resolution map of islet chromatin loops using Hi-C assays in three islet samples and use loops to annotate target genes of islet enhancers defined using ATAC-seq and published ChIP-seq data. We identify candidate target genes for thousands of islet enhancers, and find that enhancer looping is correlated with islet-specific gene expression. We fine-map T2D risk variants affecting islet enhancers, and find that candidate target genes of these variants defined using chromatin looping and eQTL mapping are enriched in protein transport and secretion pathways. At IGF2BP2, a fine-mapped T2D variant reduces islet enhancer activity and IGF2BP2 expression, and conditional inactivation of IGF2BP2 in mouse islets impairs glucose-stimulated insulin secretion. Our findings provide a resource for studying islet enhancer function and identifying genes involved in T2D risk. Risk loci for type 2 diabetes (T2D) reside in pancreatic islet enhancers. Here, the authors generate high-resolution maps of islet chromatin conformation using Hi-C which they combine with ATAC-seq and ChIP-seq data to annotate candidate target genes of enhancers and validate IGF2BP2 activity in mouse islets.
         datePublished:2019-05-07T00:00:00Z
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            Diabetes
            Epigenomics
            Genetics research
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            Humanities and Social Sciences
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      headline:Pancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk
      description:Genetic variants affecting pancreatic islet enhancers are central to T2D risk, but the gene targets of islet enhancer activity are largely unknown. We generate a high-resolution map of islet chromatin loops using Hi-C assays in three islet samples and use loops to annotate target genes of islet enhancers defined using ATAC-seq and published ChIP-seq data. We identify candidate target genes for thousands of islet enhancers, and find that enhancer looping is correlated with islet-specific gene expression. We fine-map T2D risk variants affecting islet enhancers, and find that candidate target genes of these variants defined using chromatin looping and eQTL mapping are enriched in protein transport and secretion pathways. At IGF2BP2, a fine-mapped T2D variant reduces islet enhancer activity and IGF2BP2 expression, and conditional inactivation of IGF2BP2 in mouse islets impairs glucose-stimulated insulin secretion. Our findings provide a resource for studying islet enhancer function and identifying genes involved in T2D risk. Risk loci for type 2 diabetes (T2D) reside in pancreatic islet enhancers. Here, the authors generate high-resolution maps of islet chromatin conformation using Hi-C which they combine with ATAC-seq and ChIP-seq data to annotate candidate target genes of enhancers and validate IGF2BP2 activity in mouse islets.
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         Diabetes
         Epigenomics
         Genetics research
         Science
         Humanities and Social Sciences
         multidisciplinary
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            address:
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               type:PostalAddress
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            name:Department of Cellular and Molecular Medicine
            address:
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      name:Bing Ren
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            address:
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               type:PostalAddress
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            name:Center for Epigenomics
            address:
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            address:
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      name:Kyle J. Gaulton
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            address:
               name:Department of Pediatrics, La Jolla, USA
               type:PostalAddress
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      email:[email protected]
PostalAddress:
      name:Bioinformatics and Systems Biology Graduate Program, La Jolla, USA
      name:Biomedical Sciences Graduate Program, La Jolla, USA
      name:Ludwig Institute for Cancer Research, La Jolla, USA
      name:Department of Medical Biochemistry and Biophysics, Division of Functional Genomics and Systems Biology, Karolinska Institutet, Stockholm, Sweden
      name:Bioinformatics and Systems Biology Graduate Program, La Jolla, USA
      name:Ludwig Institute for Cancer Research, La Jolla, USA
      name:Department of Molecular and Cellular Biology, Harvard University, Cambridge, USA
      name:Department of Pediatrics, La Jolla, USA
      name:Center for Epigenomics, La Jolla, USA
      name:Department of Pediatrics, La Jolla, USA
      name:Bioinformatics and Systems Biology Graduate Program, La Jolla, USA
      name:Center for Epigenomics, La Jolla, USA
      name:Department of Pediatrics, La Jolla, USA
      name:Department of Molecular and Cellular Biology, Harvard University, Cambridge, USA
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      name:Department of Pediatrics, La Jolla, USA
      name:European Molecular Biology Laboratory, Mouse Biology Unit, Monterotondo, Italy
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      name:European Molecular Biology Laboratory, Mouse Biology Unit, Monterotondo, Italy
      name:Department of Pharmacology, University of Oxford, Oxford, UK
      name:Center for Epigenomics, La Jolla, USA
      name:Department of Molecular and Cellular Biology, Harvard University, Cambridge, USA
      name:Department of Pediatrics, La Jolla, USA
      name:Department of Pediatrics, La Jolla, USA
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      name:Ludwig Institute for Cancer Research, La Jolla, USA
      name:Center for Epigenomics, La Jolla, USA
      name:Department of Cellular and Molecular Medicine, La Jolla, USA
      name:Department of Pediatrics, La Jolla, USA

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