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

TY - JOUR

T1 - Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density

AU - Barres, Romain

AU - Osler, Megan E

AU - Yan, Jie

AU - Rune, Anna

AU - Fritz, Tomas

AU - Caidahl, Kenneth

AU - Krook, Anna

AU - Zierath, Juleen R

PY - 2009/9

Y1 - 2009/9

N2 - 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.

AB - 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.

KW - Base Sequence

KW - CpG Islands

KW - DNA (Cytosine-5-)-Methyltransferase

KW - DNA Methylation

KW - DNA, Mitochondrial

KW - Diabetes Mellitus, Type 2

KW - Fatty Acids

KW - Heat-Shock Proteins

KW - Humans

KW - Mitochondria

KW - Muscle Cells

KW - Promoter Regions, Genetic

KW - RNA, Messenger

KW - RNA, Small Interfering

KW - Transcription Factors

KW - Tumor Necrosis Factor-alpha

U2 - 10.1016/j.cmet.2009.07.011

DO - 10.1016/j.cmet.2009.07.011

M3 - Journal article

C2 - 19723495

SN - 1550-4131

VL - 10

SP - 189

EP - 198

JO - Cell Metabolism

JF - Cell Metabolism

IS - 3

ER -