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Non-CpG methylation of the PGC-1α promoter through DNMT3B controls mitochondrial density.
Open accessAbstract
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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“In turn, PGC-1␣ expression may also be reduced as a consequence of promoter methylation (146) or caused by insulin itself (145), obesity (126), and sustained lipid exposure (126).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [146]
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Metadata
- 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.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 10
- Issue
- 3
- Pages
- 189-198
- ISSN
- 1550-4131 (ISSN-L)
- 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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