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

Cell Metab. 2009 Sep;10(3):189-98. doi: 10.1016/j.cmet.2009.07.011.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • CpG Islands / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism*
  • DNA Methylation*
  • DNA, Mitochondrial / metabolism
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Fatty Acids / pharmacology
  • Heat-Shock Proteins / genetics*
  • Heat-Shock Proteins / metabolism
  • Humans
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Mitochondria / 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*
  • Transcription Factors / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • DNA, Mitochondrial
  • Fatty Acids
  • Heat-Shock Proteins
  • PPARGC1A protein, human
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • RNA, Messenger
  • RNA, Small Interfering
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3B