Non-CpG Methylation of the PGC-1α Promoter through DNMT3B Controls Mitochondrial Density
Non-CpG Methylation of the PGC-1α Promoter through DNMT3B Controls Mitochondrial Density
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DOI：
10.1016/j.cmet.2009.07.011
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发表时间：
2009-09-02
期刊：
影响因子：
29
通讯作者：
Zierath, Juleen R.
中科院分区：
文献类型：
--
作者：
Barres, Romain;Osler, Megan E.;Zierath, Juleen R.
通过DNA甲基化的表观遗传修饰与代谢疾病有关。利用正常葡萄糖耐受和2型糖尿病受试者骨骼肌的全基因组启动子甲基化分析，我们确定了糖尿病受试者中过氧化物酶体增殖物激活受体γ（PPAR γ）共激活因子-1 α（PGC-1 α）的胞嘧啶超甲基化。甲基化水平与PGC-1 α mRNA和线粒体DNA（mtDNA）呈负相关。亚硫酸氢盐测序显示，在非CpG核苷酸中发现PGC-1 α内胞嘧啶甲基化的最高比例。暴露于肿瘤坏死因子-α（TNF-α）或游离脂肪酸，而不是胰岛素或葡萄糖，会使人肌管中的非CpG甲基化急剧增加。选择性沉默DNA甲基转移酶3B（DNMT 3B），而不是DNMT 1或DNMT 3A，阻止棕榈酸诱导的PGC-1 α非CpG甲基化，并降低mtDNA和PGC-1 α mRNA。我们提供了PGC-1 α高甲基化的证据，伴随着2型糖尿病患者线粒体含量的减少，并将DNMT 3B与急性脂肪酸诱导的PGC-1 α启动子非CpG甲基化联系起来。
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 (PPAR gamma) coactivator-1 alpha (PGC-1 alpha) in diabetic subjects. Methylation levels were negatively correlated with PGC-1 alpha mRNA and mitochondrial DNA (mtDNA). Bisulfite sequencing revealed that the highest proportion of cytosine methylation within PGC-1 alpha 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-1 alpha and decreased mtDNA and PGC-1 alpha mRNA. We provide evidence for PGC-1 alpha 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-1 alpha promoter.