Format

Send to

Choose Destination
Nat Commun. 2019 May 7;10(1):2078. doi: 10.1038/s41467-019-09975-4.

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

Author information

1
Bioinformatics and Systems Biology Graduate Program, UC San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
2
Biomedical Sciences Graduate Program, UC San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
3
Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
4
Department of Medical Biochemistry and Biophysics, Division of Functional Genomics and Systems Biology, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
5
Department of Molecular and Cellular Biology, Harvard University, 52 Oxford Street, Cambridge, MA, 02138, USA.
6
Department of Pediatrics, UC San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
7
Center for Epigenomics, UC San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
8
European Molecular Biology Laboratory, Mouse Biology Unit, Via Ramarini 32, 00015, Monterotondo, Italy.
9
Department of Pharmacology, University of Oxford, OX1 3QT, Oxford, UK.
10
Department of Cellular and Molecular Medicine, UC San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
11
Department of Pediatrics, UC San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. kgaulton@ucsd.edu.

Abstract

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.

PMID:
31064983
PMCID:
PMC6505525
DOI:
10.1038/s41467-019-09975-4
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center