Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients

Henriette Kirchner; Indranil Sinha; Hui Gao; Maxwell A. Ruby; Milena Schönke; Jessica M. Lindvall; Romain Barrès; Anna Krook; Erik Näslund; Karin Dahlman-Wright; Juleen R. Zierath

doi:10.1016/j.molmet.2015.12.004

Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients

Henriette Kirchner, Indranil Sinha, Hui Gao, Maxwell A. Ruby, Milena Schönke, Jessica M. Lindvall, Romain Barrès, Anna Krook, Erik Näslund, Karin Dahlman-Wright, Juleen R. Zierath^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Medizinische Klinik I

113 Zitate (Scopus)

Abstract

Objective: Epigenetic modifications contribute to the etiology of type 2 diabetes. Method: We performed genome-wide methylome and transcriptome analysis in liver from severely obese men with or without type 2 diabetes and non-obese men to discover aberrant pathways underlying the development of insulin resistance. Results were validated by pyrosequencing. Result: We identified hypomethylation of genes involved in hepatic glycolysis and insulin resistance, concomitant with increased mRNA expression and protein levels. Pyrosequencing revealed the CpG-site within ATF-motifs was hypomethylated in four of these genes in liver of severely obese non-diabetic and type 2 diabetic patients, suggesting epigenetic regulation of transcription by altered ATF-DNA binding. Conclusion: Severely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome, with hypomethylation of several genes controlling glucose metabolism within the ATF-motif regulatory site. Obesity appears to shift the epigenetic program of the liver towards increased glycolysis and lipogenesis, which may exacerbate the development of insulin resistance.

Originalsprache	Englisch
Zeitschrift	Molecular Metabolism
Jahrgang	5
Ausgabenummer	3
Seiten (von - bis)	171-183
Seitenumfang	13
ISSN	2212-8778
DOIs	https://doi.org/10.1016/j.molmet.2015.12.004
Publikationsstatus	Veröffentlicht - 01.03.2016

Fördermittel

The authors thank Dr. Carsten Daub from SciLifeLab, Science for Life Laboratory, Solna, Sweden and Rasmus Sjögren, Karolinska Institutet, for their advice regarding the genome-wide data analysis. H.K. is supported by an EMBO long-term fellowship. This work was supported by grants from the Thurings Stiftelse, The Tore Nilson Stiftelse, The Strategic Diabetes Program at Karolinska Institutet , Cardiovascular Research Program at Karolinska Institutet, European Research Council Ideas Program (ICEBERG, ERC-2008-AdG23285), Swedish Research Council ( 2011-3550 ), Swedish Diabetes Foundation ( DIA2012-082 ), Swedish Foundation for Strategic Research ( SRL10-0027 ), and Stockholm County Council ( 2012-0086 ) supported this research. Gene expression profiling and DNA-methylation assays were performed at the Bioinformatics and Expression Analysis core facility ( www.bea.ki.se ). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Foundation ( www.metabol.ku.dk ).

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Forschungsschwerpunkt: Gehirn, Hormone, Verhalten - Center for Brain, Behavior and Metabolism (CBBM)

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10.1016/j.molmet.2015.12.004

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title = "Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients",

abstract = "Objective: Epigenetic modifications contribute to the etiology of type 2 diabetes. Method: We performed genome-wide methylome and transcriptome analysis in liver from severely obese men with or without type 2 diabetes and non-obese men to discover aberrant pathways underlying the development of insulin resistance. Results were validated by pyrosequencing. Result: We identified hypomethylation of genes involved in hepatic glycolysis and insulin resistance, concomitant with increased mRNA expression and protein levels. Pyrosequencing revealed the CpG-site within ATF-motifs was hypomethylated in four of these genes in liver of severely obese non-diabetic and type 2 diabetic patients, suggesting epigenetic regulation of transcription by altered ATF-DNA binding. Conclusion: Severely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome, with hypomethylation of several genes controlling glucose metabolism within the ATF-motif regulatory site. Obesity appears to shift the epigenetic program of the liver towards increased glycolysis and lipogenesis, which may exacerbate the development of insulin resistance.",

author = "Henriette Kirchner and Indranil Sinha and Hui Gao and Ruby, \{Maxwell A.\} and Milena Sch{\"o}nke and Lindvall, \{Jessica M.\} and Romain Barr{\`e}s and Anna Krook and Erik N{\"a}slund and Karin Dahlman-Wright and Zierath, \{Juleen R.\}",

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doi = "10.1016/j.molmet.2015.12.004",

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AU - Kirchner, Henriette

AU - Sinha, Indranil

AU - Gao, Hui

AU - Ruby, Maxwell A.

AU - Schönke, Milena

AU - Lindvall, Jessica M.

AU - Barrès, Romain

AU - Krook, Anna

AU - Näslund, Erik

AU - Dahlman-Wright, Karin

AU - Zierath, Juleen R.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - Objective: Epigenetic modifications contribute to the etiology of type 2 diabetes. Method: We performed genome-wide methylome and transcriptome analysis in liver from severely obese men with or without type 2 diabetes and non-obese men to discover aberrant pathways underlying the development of insulin resistance. Results were validated by pyrosequencing. Result: We identified hypomethylation of genes involved in hepatic glycolysis and insulin resistance, concomitant with increased mRNA expression and protein levels. Pyrosequencing revealed the CpG-site within ATF-motifs was hypomethylated in four of these genes in liver of severely obese non-diabetic and type 2 diabetic patients, suggesting epigenetic regulation of transcription by altered ATF-DNA binding. Conclusion: Severely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome, with hypomethylation of several genes controlling glucose metabolism within the ATF-motif regulatory site. Obesity appears to shift the epigenetic program of the liver towards increased glycolysis and lipogenesis, which may exacerbate the development of insulin resistance.

AB - Objective: Epigenetic modifications contribute to the etiology of type 2 diabetes. Method: We performed genome-wide methylome and transcriptome analysis in liver from severely obese men with or without type 2 diabetes and non-obese men to discover aberrant pathways underlying the development of insulin resistance. Results were validated by pyrosequencing. Result: We identified hypomethylation of genes involved in hepatic glycolysis and insulin resistance, concomitant with increased mRNA expression and protein levels. Pyrosequencing revealed the CpG-site within ATF-motifs was hypomethylated in four of these genes in liver of severely obese non-diabetic and type 2 diabetic patients, suggesting epigenetic regulation of transcription by altered ATF-DNA binding. Conclusion: Severely obese non-diabetic and type 2 diabetic patients have distinct alterations in the hepatic methylome and transcriptome, with hypomethylation of several genes controlling glucose metabolism within the ATF-motif regulatory site. Obesity appears to shift the epigenetic program of the liver towards increased glycolysis and lipogenesis, which may exacerbate the development of insulin resistance.

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VL - 5

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JO - Molecular Metabolism

JF - Molecular Metabolism

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Altered DNA methylation of glycolytic and lipogenic genes in liver from obese and type 2 diabetic patients

Abstract

Fördermittel

UN SDGs

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