Cited by 607Epigenetics and DNA MethylationMetabolism, Diabetes, and CancerGenomics and Chromatin Dynamics

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Non-CpG methylation of the PGC-1α promoter through DNMT3B controls mitochondrial density.

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Barrès, Romain, Osler, Megan E., Yan, Jie, Rune, Anna, Fritz, Tomas, Caidahl, Kenneth, Krook, Anna, Zierath, Juleen R.·2009·Cell Metabolism

DOI 10.1016/j.cmet.2009.07.011

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Abstract

Epigenetic modification through DNA methylation is implicated in metabolic disease. Using whole-genome promoter methylation analysis of skeletal muscle from normal glucose-tolerant and type 2 diabetic subjects, we identified cytosine hypermethylation of peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 alpha (PGC-1alpha) in diabetic subjects. Methylation levels were negatively correlated with PGC-1alpha mRNA and mitochondrial DNA (mtDNA). Bisulfite sequencing revealed that the highest proportion of cytosine methylation within PGC-1alpha was found within non-CpG nucleotides. Non-CpG methylation was acutely increased in human myotubes by exposure to tumor necrosis factor-alpha (TNF-alpha) or free fatty acids, but not insulin or glucose. Selective silencing of the DNA methyltransferase 3B (DNMT3B), but not DNMT1 or DNMT3A, prevented palmitate-induced non-CpG methylation of PGC-1alpha and decreased mtDNA and PGC-1alpha mRNA. We provide evidence for PGC-1alpha hypermethylation, concomitant with reduced mitochondrial content in type 2 diabetic patients, and link DNMT3B to the acute fatty-acid-induced non-CpG methylation of PGC-1alpha promoter.

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Authors: Barrès, R., Osler, M. E., Yan, J., Rune, A., Fritz, T., Caidahl, K., Krook, A., & Zierath, J. R.
Affiliations: Karolinska University Hospital (SE)
Corresponding author: Zierath, Juleen R.
ORCID: Barrès, Romain
Yan, Jie
Caidahl, Kenneth
Krook, Anna
Zierath, Juleen R.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2009-09
Volume: 10
Issue: 3
Pages: 189-198
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2009.07.011
OpenAlex: W1985280131
Semantic Scholar: 4a04e95dbe0297f0a51059b2ab7890362fad1e57
Cited by: 602
References: 44
Citations by year: 2026: 26 · 2025: 16 · 2024: 27 · 2023: 24 · 2022: 26 · 2021: 37 · 2020: 24 · 2019: 35 · 2018: 36 · 2017: 41 · 2016: 50 · 2015: 57 · 2014: 49 · 2013: 43 · 2012: 39
FWCI: 14.88
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1451 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
Funders: Novo Nordisk UK Research Foundation
Vetenskapsrådet
European Commission (LSHM-CT-2004-005272, LSHM-CT-2004-512013 EUGENE2)
European Research Council
European Foundation for the Study of Diabetes
Knut och Alice Wallenbergs Stiftelse
Glenn Foundation for Medical Research
Stockholms Läns Landsting
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords: PGC-1α, DNMT3B, promoter methylation, mitochondrial density, type 2 diabetes, skeletal muscle, mitochondrial DNA, free fatty acids, palmitate, TNF-α, myotubes, DNA methyltransferases, epigenetic regulation
MeSH terms: Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, DNA Methyltransferase 3B, Base Sequence, Diabetes Mellitus, Type 2, DNA (Cytosine-5-)-Methyltransferases, DNA, Mitochondrial, Fatty Acids, Heat-Shock Proteins, Humans, Mitochondria, Promoter Regions, Genetic, RNA, Messenger, Transcription Factors, Tumor Necrosis Factor-alpha, CpG Islands, DNA Methylation, Muscle Cells, RNA, Small Interfering

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Non-CpG methylation of the PGC-1α promoter through DNMT3B controls mitochondrial density.

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