Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density
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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.
Original language | English |
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Journal | Cell Metabolism |
Volume | 10 |
Issue number | 3 |
Pages (from-to) | 189-98 |
Number of pages | 10 |
ISSN | 1550-4131 |
DOIs | |
Publication status | Published - Sep 2009 |
- Base Sequence, CpG Islands, DNA (Cytosine-5-)-Methyltransferase, DNA Methylation, DNA, Mitochondrial, Diabetes Mellitus, Type 2, Fatty Acids, Heat-Shock Proteins, Humans, Mitochondria, Muscle Cells, Promoter Regions, Genetic, RNA, Messenger, RNA, Small Interfering, Transcription Factors, Tumor Necrosis Factor-alpha
Research areas
ID: 45577358