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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)

Nyckelord

Base Sequence

CpG Islands/genetics

DNA (Cytosine-5-)-Methyltransferases/*metabolism

*DNA Methylation

DNA

Mitochondrial/metabolism

Diabetes Mellitus

Type 2/*genetics/metabolism/pathology

Fatty Acids/pharmacology

Heat-Shock Proteins/*genetics/metabolism

Humans

Mitochondria/*genetics/metabolism/ultrastructure

Muscle Cells/metabolism

Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha

Promoter Regions

Genetic

RNA

Messenger/metabolism

RNA

Small Interfering/metabolism

Transcription Factors/*genetics/metabolism

Tumor Necrosis Factor-alpha/pharmacology

Publikations- och innehållstyp

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