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Whole-genome Bisulfite Sequencing of Human Pancreatic Islets Reveals Novel Differentially Methylated Regions in Type 2 Diabetes Pathogenesis

Volkov, Petr LU ; Bacos, Karl LU ; Ofori, Jones K LU ; Esguerra, Jonathan Lou S LU ; Eliasson, Lena LU ; Rönn, Tina LU and Ling, Charlotte LU (2017) In Diabetes 66(4). p.1074-1085
Abstract

Current knowledge about the role of epigenetics in type 2 diabetes (T2D) remains limited. Only a few studies have investigated DNA methylation of selected candidate genes or a very small fraction of genomic CpG sites in human pancreatic islets, the tissue of primary pathogenic importance for diabetes. Our aim was to characterize the whole-genome DNA methylation landscape in human pancreatic islets, to identify differentially methylated regions (DMRs) in diabetic islets, and to investigate the function of DMRs in islet biology.Here, we performed whole-genome bisulfite sequencing, which is a comprehensive and unbiased method to study DNA methylation throughout the genome on a single nucleotide resolution, in pancreatic islets from donors... (More)

Current knowledge about the role of epigenetics in type 2 diabetes (T2D) remains limited. Only a few studies have investigated DNA methylation of selected candidate genes or a very small fraction of genomic CpG sites in human pancreatic islets, the tissue of primary pathogenic importance for diabetes. Our aim was to characterize the whole-genome DNA methylation landscape in human pancreatic islets, to identify differentially methylated regions (DMRs) in diabetic islets, and to investigate the function of DMRs in islet biology.Here, we performed whole-genome bisulfite sequencing, which is a comprehensive and unbiased method to study DNA methylation throughout the genome on a single nucleotide resolution, in pancreatic islets from donors with T2D and non-diabetic controls. We identified 25,820 DMRs in islets from individuals with T2D. These DMRs cover loci with known islet function e.g. PDX1, TCF7L2 and ADCY5 Importantly, binding sites previously identified by ChIP-seq for islet-specific transcription factors, enhancer regions and different histone marks were enriched in the T2D associated DMRs. We also identified 457 genes, including NR4A3, PARK2, PID1, SLC2A2 and SOCS2 that had both DMRs and significant expression changes in T2D islets. To mimic the situation in T2D islets, candidate genes were overexpressed or silenced in cultured β-cells. This resulted in impaired insulin secretion, thereby connecting differential methylation to islet dysfunction. We further explored the islet methylome and found a strong link between methylation levels and histone marks. Additionally, DNA methylation in different genomic regions and of different transcript types (i.e. protein-coding, non-coding and pseudogenes) was associated with islet expression levels.Our study provides a comprehensive picture of the islet DNA methylome in both non-diabetic and diabetic individuals and highlights the importance of epigenetic dysregulation in pancreatic islets and T2D pathogenesis.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
66
issue
4
pages
1074 - 1085
publisher
American Diabetes Association Inc.
external identifiers
  • scopus:85019618381
ISSN
1939-327X
DOI
10.2337/db16-0996
language
English
LU publication?
yes
id
f0628ee1-4239-4787-9f3d-22979258146c
date added to LUP
2017-03-22 10:58:03
date last changed
2018-09-16 04:44:40
@article{f0628ee1-4239-4787-9f3d-22979258146c,
  abstract     = {<p>Current knowledge about the role of epigenetics in type 2 diabetes (T2D) remains limited. Only a few studies have investigated DNA methylation of selected candidate genes or a very small fraction of genomic CpG sites in human pancreatic islets, the tissue of primary pathogenic importance for diabetes. Our aim was to characterize the whole-genome DNA methylation landscape in human pancreatic islets, to identify differentially methylated regions (DMRs) in diabetic islets, and to investigate the function of DMRs in islet biology.Here, we performed whole-genome bisulfite sequencing, which is a comprehensive and unbiased method to study DNA methylation throughout the genome on a single nucleotide resolution, in pancreatic islets from donors with T2D and non-diabetic controls. We identified 25,820 DMRs in islets from individuals with T2D. These DMRs cover loci with known islet function e.g. PDX1, TCF7L2 and ADCY5 Importantly, binding sites previously identified by ChIP-seq for islet-specific transcription factors, enhancer regions and different histone marks were enriched in the T2D associated DMRs. We also identified 457 genes, including NR4A3, PARK2, PID1, SLC2A2 and SOCS2 that had both DMRs and significant expression changes in T2D islets. To mimic the situation in T2D islets, candidate genes were overexpressed or silenced in cultured β-cells. This resulted in impaired insulin secretion, thereby connecting differential methylation to islet dysfunction. We further explored the islet methylome and found a strong link between methylation levels and histone marks. Additionally, DNA methylation in different genomic regions and of different transcript types (i.e. protein-coding, non-coding and pseudogenes) was associated with islet expression levels.Our study provides a comprehensive picture of the islet DNA methylome in both non-diabetic and diabetic individuals and highlights the importance of epigenetic dysregulation in pancreatic islets and T2D pathogenesis.</p>},
  author       = {Volkov, Petr and Bacos, Karl and Ofori, Jones K and Esguerra, Jonathan Lou S and Eliasson, Lena and Rönn, Tina and Ling, Charlotte},
  issn         = {1939-327X},
  language     = {eng},
  month        = {01},
  number       = {4},
  pages        = {1074--1085},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Whole-genome Bisulfite Sequencing of Human Pancreatic Islets Reveals Novel Differentially Methylated Regions in Type 2 Diabetes Pathogenesis},
  url          = {http://dx.doi.org/10.2337/db16-0996},
  volume       = {66},
  year         = {2017},
}