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

Romain Barres, Megan E Osler, Jie Yan, Anna Rune, Tomas Fritz, Kenneth Caidahl, Anna Krook, Juleen R Zierath

    413 Citations (Scopus)

    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 languageEnglish
    JournalCell Metabolism
    Volume10
    Issue number3
    Pages (from-to)189-98
    Number of pages10
    ISSN1550-4131
    DOIs
    Publication statusPublished - 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

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