Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo 153-8902, Japan.
Nat Commun. 2013;4:2262. doi: 10.1038/ncomms3262.
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-γ (PPARγ) has the ability to direct local demethylation around its binding sites, the PPAR response elements (PPREs), during adipocyte differentiation. PPARγ is a key regulator of the differentiation process that forms a PPARγ 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.
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）来实现的。然而，在其基因组背景下，去甲基化的靶区如何被区分开来仍不清楚。在这里，我们表明核受体过氧化物酶体增殖物激活受体-γ（PPARγ）在脂肪细胞分化过程中具有在其结合位点（PPAR 反应元件，PPREs）周围进行局部去甲基化的能力。PPARγ 是分化过程的关键调节因子，它在 PPREs 上形成 PPARγ 共激活因子复合物，并激活脂肪细胞特异性基因的表达。该复合物在 PPREs 上发生聚（ADP-核糖）化（PAR 化），并且 Tet 蛋白通过其结合 PAR 聚合物的能力局部催化 5mC 向 5hmC 的转化，从而诱导特定区域的去甲基化。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 蛋白识别 DNA 去甲基化位点的地标。
