Effects of palmitate on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets

Hall, Elin, Volkov, Petr, Dayeh, Tasnim, Bacos, Karl, Ronn, Tina, Nitert, Marloes Dekker and Ling, Charlotte (2014) Effects of palmitate on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets. BMC Medicine, 12 103: 1-15. doi:10.1186/1741-7015-12-103


Author Hall, Elin
Volkov, Petr
Dayeh, Tasnim
Bacos, Karl
Ronn, Tina
Nitert, Marloes Dekker
Ling, Charlotte
Title Effects of palmitate on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets
Journal name BMC Medicine   Check publisher's open access policy
ISSN 1741-7015
Publication date 2014-05-23
Year available 2014
Sub-type Article (original research)
DOI 10.1186/1741-7015-12-103
Open Access Status DOI
Volume 12
Issue 103
Start page 1
End page 15
Total pages 15
Place of publication London, United Kingdom
Publisher BioMed Central
Collection year 2015
Language eng
Formatted abstract
Background: Circulating free fatty acids are often elevated in patients with type 2 diabetes (T2D) and obese individuals. Chronic exposure to high levels of saturated fatty acids has detrimental effects on islet function and insulin secretion. Altered gene expression and epigenetics may contribute to T2D and obesity. However, there is limited information on whether fatty acids alter the genome-wide transcriptome profile in conjunction with DNA methylation patterns in human pancreatic islets. To dissect the molecular mechanisms linking lipotoxicity to impaired insulin secretion, we investigated the effects of a 48 h palmitate treatment in vitro on genome-wide mRNA expression and DNA methylation patterns in human pancreatic islets.

Methods: Genome-wide mRNA expression was analyzed using Affymetrix GeneChip® Human Gene 1.0 ST whole transcript-based array (n = 13) and genome-wide DNA methylation was analyzed using Infinium HumanMethylation450K BeadChip (n = 13) in human pancreatic islets exposed to palmitate or control media for 48 h. A non-parametric paired Wilcoxon statistical test was used to analyze mRNA expression. Apoptosis was measured using Apo-ONE® Homogeneous Caspase-3/7 Assay (n = 4).

Results: While glucose-stimulated insulin secretion was decreased, there was no significant effect on apoptosis in human islets exposed to palmitate. We identified 1,860 differentially expressed genes in palmitate-treated human islets. These include candidate genes for T2D, such as TCF7L2, GLIS3, HNF1B and SLC30A8. Additionally, genes in glycolysis/gluconeogenesis, pyruvate metabolism, fatty acid metabolism, glutathione metabolism and one carbon pool by folate were differentially expressed in palmitate-treated human islets. Palmitate treatment altered the global DNA methylation level and DNA methylation levels of CpG island shelves and shores, 5′UTR, 3′UTR and gene body regions in human islets. Moreover, 290 genes with differential expression had a corresponding change in DNA methylation, for example, TCF7L2 and GLIS3. Importantly, out of the genes differentially expressed due to palmitate treatment in human islets, 67 were also associated with BMI and 37 were differentially expressed in islets from T2D patients.

Conclusion: Our study demonstrates that palmitate treatment of human pancreatic islets gives rise to epigenetic modifications that together with altered gene expression may contribute to impaired insulin secretion and T2D.
Keyword Palmitate
Human pancreatic islets
Type 2 diabetes
Lipotoxicity
DNA methylation
mRNA expression
Insulin secretion
Epigenetics
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
 
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