Increased Expression of DNA Methyltransferase 3a in Obese Adipose Tissue: Studies With Transgenic Mice
Increased Expression of DNA Methyltransferase 3a in Obese Adipose Tissue: Studies With Transgenic Mice
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DOI：
10.1038/oby.2009.246
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发表时间：
2010-02-10
期刊：
影响因子：
6.9
通讯作者：
Ogawa, Yoshihiro
中科院分区：
文献类型：
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作者：
Kamei, Yasutomi;Suganami, Takayoshi;Ogawa, Yoshihiro
表观遗传机制可能参与肥胖的发展。本研究旨在研究DNA甲基转移酶（Dnmt 3a）在肥胖脂肪组织中的作用。实时荧光定量PCR检测Dnmts基因表达。产生在脂肪组织中由aP 2启动子驱动过表达Dnmt 3a的转基因小鼠（Dnmt 3a小鼠）。使用亚硫酸氢盐DNA甲基化分析检测下调基因的DNA甲基化。对Dnmt 3a小鼠饲喂添加甲基的饮食或高脂肪饮食，并进行体重测量和脂肪组织的基因表达分析。肥胖小鼠脂肪组织中Dnmt 3a的表达显著上调。Dnmt 3a小鼠的互补DNA（cDNA）微阵列分析显示分泌型卷曲相关蛋白1（SFRP 1）的基因表达略有下降，而干扰素应答因子9（IRF 9）的基因表达显著增加。在SFRP 1启动子中，DNA甲基化在Dnmt 3a小鼠中相对于野生型小鼠没有显著增加。在高脂肪饮食或甲基补充饮食的实验中，体重没有显着差异的基因型。炎症细胞因子如肿瘤坏死因子-α（TNF-α）和单核细胞趋化蛋白-1（MCP-1）的基因表达水平在Dnmt 3a小鼠中高于高脂饮食的野生型小鼠。这项研究表明，脂肪组织中Dnmt 3a的表达增加可能有助于肥胖相关的炎症。这些数据突出了Dnmt 3a在成人组织以及发育中的胚胎和癌症中的潜在作用。
Epigenetic mechanisms are likely to be involved in the development of obesity. This study was designed to examine the role of a DNA methyltransferase (Dnmt3a), in obese adipose tissue. The gene expression of Dnmts was examined by quantitative real-time PCR analysis. Transgenic mice overexpressing Dnmt3a in the adipose tissue driven by the aP2 promoter were created (Dnmt3a mice). DNA methylation of downregulated genes was examined using bisulfite DNA methylation analysis. Dnmt3a mice were fed a methyl-supplemented or high-fat diet, and subjected to body weight measurement and gene expression analysis of the adipose tissue. Expression of Dnmt3a was markedly upregulated in the adipose tissue of obese mice. The complementary DNA (cDNA) microarray analysis of Dnmt3a mice revealed a slight decrease in the gene expression of secreted frizzled-related protein 1 (SFRP1) and marked increase in that of interferon responsive factor 9 (IRF9). In the SFRP1 promoter, DNA methylation was not markedly increased in Dnmt3a mice relative to wild-type mice. In experiments with a high-fat diet or methyl-supplemented diet, body weight did not differ significantly with the genotypes. Gene expression levels of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-1) were higher in Dnmt3a mice than in wild-type mice on a high-fat diet. This study suggests that increased expression of Dnmt3a in the adipose tissue may contribute to obesity-related inflammation. The data highlight the potential role of Dnmt3a in the adult tissue as well as in the developing embryo and cancer.