PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine
PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine
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DOI：
10.1038/ncomms3262
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发表时间：
2013-08-01
影响因子：
16.6
通讯作者：
Murata, Masayuki
中科院分区：
文献类型：
--
作者：
Fujiki, Katsunori;Shinoda, Akihiro;Murata, Masayuki
最近的研究表明，DNA 去甲基化是通过 Tet 蛋白将 5-甲基胞嘧啶 (5mC) 转化为 5-羟甲基胞嘧啶 (5hmC) 进行的。然而，目前尚不清楚去甲基化的目标区域在其基因组背景下如何区分。在这里，我们表明，在脂肪细胞分化过程中，核受体过氧化物酶体增殖物激活受体-γ（PPARγ）能够指导其结合位点（PPAR反应元件（PPRE））周围的局部去甲基化。 PPAR γ 是分化过程的关键调节因子，在 PPRE 上形成 PPAR γ 共激活剂复合物并激活脂肪细胞特异性基因的表达。该复合物在 PPRE 上被聚（ADP-核糖基）化（PARylated），Tet 蛋白通过其与 PAR 聚合物结合的能力，局部催化 5mC 转化为 5hmC，从而诱导区域特异性去甲基化。我们的研究表明，序列依赖性转录因子复合物可以通过其翻译后修饰，作为 Tet 蛋白的标志来识别 DNA 去甲基化位点。
Recent studies have shown that DNA demethylation goes through the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by Tet proteins. However, it is still unclear how the target regions for demethylation are distinguished within their genomic context. Here we show that the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR gamma) has the ability to direct local demethylation around its binding sites, the PPAR response elements (PPREs), during adipocyte differentiation. PPAR gamma is a key regulator of the differentiation process that forms a PPAR gamma co-activator complex on PPREs and activates the expression of adipocyte-specific genes. The complex is poly(ADP-ribosyl)ated (PARylated) on PPREs, and Tet proteins catalyse the conversion of 5mC to 5hmC locally by their ability to bind to the PAR polymer, thereby inducing region-specific demethylation. Our study demonstrates that a sequence-dependent transcription factor complex can, through its post-translational modification, serve for Tet proteins as a landmark to identify sites of DNA demethylation.