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

William W. Greenwald; Joshua Chiou; Jian Yan; Yunjiang Qiu; Ning Dai; Allen Wang; Naoki Nariai; Anthony Aylward; Jee Yun Han; Nikita Kadakia; Laura Regue; Mei-Lin Okino; Frauke Drees; Dana Kramer; Nicholas Vinckier; Liliana Minichiello; David Gorkin; Joseph Avruch; Kelly A. Frazer; Maike Sander; Bing Ren; Kyle J. Gaulton

doi:10.1038/s41467-019-09975-4

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

William W. Greenwald
, Joshua Chiou
, Jian Yan
, Yunjiang Qiu
, Ning Dai
, Allen Wang
, Naoki Nariai
, Anthony Aylward
, Jee Yun Han
, Nikita Kadakia
, Laura Regue
, Mei-Lin Okino
, Frauke Drees
, Dana Kramer
, Nicholas Vinckier
, Liliana Minichiello
, David Gorkin
, Joseph Avruch
, Kelly A. Frazer
, Maike Sander

Bing Ren, Kyle J. Gaulton^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

78 Citations (Scopus)

47 Downloads (CityUHK Scholars)

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.

Original language	English
Article number	2078
Number of pages	12
Journal	Nature Communications
Volume	10
Online published	7 May 2019
DOIs	https://doi.org/10.1038/s41467-019-09975-4
Publication status	Published - 7 May 2019
Externally published	Yes

Funding

Support for this work was provided by NIH funding U01DK105541 to M.S., K.A.F. and B.R., R01DK114650 to K.G., U01DK112155 to M.S. and K.A.F. and R37DK017776 and P30DK057521 to J.A., the Ludwig Institute for Cancer Research to B.R., postdoc fellowship 537-2014-6796 from the Swedish Vetenskapsradet to J.Y., fellowship F31HL142151 to W.W.G. and JDRF-3-2012-177 postdoc fellowship to A.W., D.K. and L.M. thank the EMBL-Monterotondo gene expression and transgenic services for the production of the Imp2 floxed line. L.M. was supported in part by the Lundbeck foundation (177/05) and EMBL-Mouse Biology Unit. D.K. was supported by an EMBL-postdoctoral fellowship. Funding for mouse experiments was provided by the Slim Initiative for Genomic Medicine, a project funded by the Carlos Slim Foundation in Mexico.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Keywords

GENOME-WIDE ASSOCIATION
GENE-EXPRESSION
READ ALIGNMENT
ANNOTATION
DISCOVERY
CELL
SEQ
PROVIDES
ELEMENTS
SUITE

Publisher's Copyright Statement

This full text is made available under CC-BY 4.0. https://creativecommons.org/licenses/by/4.0/

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10.1038/s41467-019-09975-4

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Greenwald, W. W., Chiou, J., Yan, J., Qiu, Y., Dai, N., Wang, A., Nariai, N., Aylward, A., Han, J. Y., Kadakia, N., Regue, L., Okino, M.-L., Drees, F., Kramer, D., Vinckier, N., Minichiello, L., Gorkin, D., Avruch, J., Frazer, K. A., ... Gaulton, K. J. (2019). Pancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk. Nature Communications, 10, Article 2078. https://doi.org/10.1038/s41467-019-09975-4

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title = "Pancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk",

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.",

keywords = "GENOME-WIDE ASSOCIATION, GENE-EXPRESSION, READ ALIGNMENT, ANNOTATION, DISCOVERY, CELL, SEQ, PROVIDES, ELEMENTS, SUITE",

author = "Greenwald, \{William W.\} and Joshua Chiou and Jian Yan and Yunjiang Qiu and Ning Dai and Allen Wang and Naoki Nariai and Anthony Aylward and Han, \{Jee Yun\} and Nikita Kadakia and Laura Regue and Mei-Lin Okino and Frauke Drees and Dana Kramer and Nicholas Vinckier and Liliana Minichiello and David Gorkin and Joseph Avruch and Frazer, \{Kelly A.\} and Maike Sander and Bing Ren and Gaulton, \{Kyle J.\}",

year = "2019",

month = may,

day = "7",

doi = "10.1038/s41467-019-09975-4",

language = "English",

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Greenwald, WW, Chiou, J, Yan, J, Qiu, Y, Dai, N, Wang, A, Nariai, N, Aylward, A, Han, JY, Kadakia, N, Regue, L, Okino, M-L, Drees, F, Kramer, D, Vinckier, N, Minichiello, L, Gorkin, D, Avruch, J, Frazer, KA, Sander, M, Ren, B & Gaulton, KJ 2019, 'Pancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk', Nature Communications, vol. 10, 2078. https://doi.org/10.1038/s41467-019-09975-4

TY - JOUR

T1 - Pancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk

AU - Greenwald, William W.

AU - Chiou, Joshua

AU - Yan, Jian

AU - Qiu, Yunjiang

AU - Dai, Ning

AU - Wang, Allen

AU - Nariai, Naoki

AU - Aylward, Anthony

AU - Han, Jee Yun

AU - Kadakia, Nikita

AU - Regue, Laura

AU - Okino, Mei-Lin

AU - Drees, Frauke

AU - Kramer, Dana

AU - Vinckier, Nicholas

AU - Minichiello, Liliana

AU - Gorkin, David

AU - Avruch, Joseph

AU - Frazer, Kelly A.

AU - Sander, Maike

AU - Ren, Bing

AU - Gaulton, Kyle J.

PY - 2019/5/7

Y1 - 2019/5/7

N2 - 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.

AB - 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.

KW - GENOME-WIDE ASSOCIATION

KW - GENE-EXPRESSION

KW - READ ALIGNMENT

KW - ANNOTATION

KW - DISCOVERY

KW - CELL

KW - SEQ

KW - PROVIDES

KW - ELEMENTS

KW - SUITE

UR - https://www.scopus.com/pages/publications/85065312876

UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-85065312876&origin=recordpage

U2 - 10.1038/s41467-019-09975-4

DO - 10.1038/s41467-019-09975-4

M3 - RGC 21 - Publication in refereed journal

C2 - 31064983

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

M1 - 2078

ER -

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

Abstract

Funding

UN SDGs

Research Keywords

Publisher's Copyright Statement

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