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.
| Original language | English |
|---|---|
| Journal | Cell Metabolism |
| Volume | 10 |
| Issue number | 3 |
| Pages (from-to) | 189-98 |
| Number of pages | 10 |
| ISSN | 1550-4131 |
| DOIs | |
| Publication status | Published - Sept 2009 |
Keywords
- 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
