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DNA羟化酶(TET1)和羟甲基胞嘧啶在转录和DNA甲基化保真度中的作用
催化胞嘧啶5位甲基化(mC)的酶在调控基因表达和维持细胞稳定中具有至关重要的作用。相关报道发现,TET1能够催化mC的甲基基团羟基化,将其转变成5羟甲基胞嘧啶(hmC)。对于此,科学家在思考TET1和hmC是如何作用于DNA甲基化和基因表达调控,并有几种不同的模型产生。在本研究中,研究者通过ChIP/DIP-seq技术,分析了基因间的表达差异和功能相关性,并结合western blot,基因敲除和免疫沉淀验证实验结果。结果显示,能够与TET1结合的基因遍及胚胎干细胞基因组,大多数结合位点位于CpG富集的启动子转录起始位点(Transcription start sites,TSSs)和基因内部。hmC修饰在基因主体(gene body)中被发现,与mC相似,也富集在CpG丰富的TSSs。研究进一步发现,TET1在转录抑制中同样起重要作用,TET1能够与一定比例的Polycomb靶基因群,参与Polycomb靶向的发育调控因子的抑制。此外,TET1与SIN3A共抑制因子复合物结合并共同起作用。最终作者得出结论,TET1可以调整转录水平、调控CpG富集序列中的异常甲基化DNA,从而有助于DNA甲基化的保真度。本研究为进一步研究羟甲基化胞嘧啶在表观遗传中的作用机理提供了新的研究思路,和重要线索。
TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity
Abstract
Enzymes catalysing the methylation of the 5-position of cytosine (mC) have essential roles in regulating gene expression and maintaining cellular identity. Recently, TET1 was found to hydroxylate the methyl group of mC, converting it to 5-hydroxymethyl cytosine (hmC). Here we show that TET1 binds throughout the genome of embryonic stem cells, with the majority of binding sites located at transcription start sites (TSSs) of CpG-rich promoters and within genes. The hmC modification is found in gene bodies and in contrast to mC is also enriched at CpG-rich TSSs. We provide evidence further that TET1 has a role in transcriptional repression. TET1 binds a significant proportion of Polycomb group target genes. Furthermore, TET1 associates and colocalizes with the SIN3A co-repressor complex. We propose that TET1 fine-tunes transcription, opposes aberrant DNA methylation at CpG-rich sequences and thereby contributes to the regulation of DNA methylation fidelity.
原文:TET1 and hydroxymethylcytosine in transcription and DNA methylation fidelity, Nature, 2011
编辑: gaowei2010