Three SRA-domain methylcytosine-binding proteins cooperate to maintain global CpG methylation and epigenetic silencing in Arabidopsis.
Three SRA-domain methylcytosine-binding proteins cooperate to maintain global CpG methylation and epigenetic silencing in Arabidopsis.
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DOI：
10.1371/journal.pgen.1000156
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发表时间：
2008-08-15
期刊：
影响因子：
4.5
通讯作者：
Richards EJ
中科院分区：
文献类型：
--
作者：
Woo HR;Dittmer TA;Richards EJ
甲基胞嘧啶结合蛋白破译由DNA甲基化编码的表观遗传信息，并提供DNA甲基化、染色质结构修饰和基因沉默之间的联系。甲基化变异体1（VIM1）编码拟南芥中SRA（SET和RING相关）结构域甲基胞嘧啶结合蛋白，VIM1功能的丧失导致着丝粒DNA低甲基化和着丝粒异染色质在分裂间期的解凝聚。在拟南芥基因组中，有五个Vim基因具有非常高的序列相似性，编码含有PHD结构域、两个RING结构域和一个SRA结构域的蛋白质。为了进一步了解Vim蛋白的功能和潜在冗余，我们研究了结合不同Vim突变的菌株和下调多个Vim家族基因的转基因Vim敲低株系。vim 1 vim 3双突变体和转基因Vim敲除株系的基因区域中的CpG位点以及异染色质区域中的重复序列显示DNA甲基化降低。此外，转录沉默被释放在这些植物中的大多数异染色质区域检查。有趣的是，vim 1 vim 3突变体和Vim敲除株系在CpG低甲基化的背景下获得了5S rRNA基因中的异位CpHpH甲基化。vim 1 vim 2 vim 3三突变体表现出异常的形态学表型，包括晚开花，这与FWA基因5′端DNA低甲基化和FWA基因沉默的解除有关。我们的研究结果表明，VIM1，VIM2和VIM3在维持全局CpG甲基化和表观遗传转录沉默方面具有重叠功能。胞嘧啶碱基的甲基化提供了叠加在基因组的核苷酸序列上的一层表观遗传信息。结合甲基化胞嘧啶并帮助维持DNA修饰的蛋白质是介导表观遗传状态记忆的自繁殖系统中的重要关键。我们以前证明，VIM 1（变异甲基化1）蛋白质从开花植物拟南芥结合DNA，含有甲基化胞嘧啶和所需的完整甲基化和压缩的着丝粒DNA。在这项研究中，我们发现VIM1与两种相关蛋白VIM2和VIM3协同工作，不仅在着丝粒而且在整个基因组中维持胞嘧啶甲基化。Vim蛋白特异性地作用于靶向CpG二核苷酸的DNA甲基化途径，而不是植物特异性的非CpG甲基化途径，其中植物与动物共享CpG二核苷酸。VIM1、VIM2和VIM3功能的丧失还导致多种序列的转录基因沉默减少，并导致异常发育表型，包括与FWA基因沉默丧失相关的晚花。我们的研究结果表明，这三个相关的Vim家族蛋白在MET 1介导的CpG甲基化途径中具有重叠的功能。
Methylcytosine-binding proteins decipher the epigenetic information encoded by DNA methylation and provide a link between DNA methylation, modification of chromatin structure, and gene silencing. VARIANT IN METHYLATION 1 (VIM1) encodes an SRA (SET- and RING-associated) domain methylcytosine-binding protein in Arabidopsis thaliana, and loss of VIM1 function causes centromere DNA hypomethylation and centromeric heterochromatin decondensation in interphase. In the Arabidopsis genome, there are five VIM genes that share very high sequence similarity and encode proteins containing a PHD domain, two RING domains, and an SRA domain. To gain further insight into the function and potential redundancy among the VIM proteins, we investigated strains combining different vim mutations and transgenic vim knock-down lines that down-regulate multiple VIM family genes. The vim1 vim3 double mutant and the transgenic vim knock-down lines showed decreased DNA methylation primarily at CpG sites in genic regions, as well as repeated sequences in heterochromatic regions. In addition, transcriptional silencing was released in these plants at most heterochromatin regions examined. Interestingly, the vim1 vim3 mutant and vim knock-down lines gained ectopic CpHpH methylation in the 5S rRNA genes against a background of CpG hypomethylation. The vim1 vim2 vim3 triple mutant displayed abnormal morphological phenotypes including late flowering, which is associated with DNA hypomethylation of the 5′ region of FWA and release of FWA gene silencing. Our findings demonstrate that VIM1, VIM2, and VIM3 have overlapping functions in maintenance of global CpG methylation and epigenetic transcriptional silencing. Methylation of cytosine bases provides one layer of epigenetic information that is superimposed on the nucleotide sequence of a genome. Proteins that bind methylated cytosines and also help maintain that DNA modification are important linchpins in a self-propagating system mediating memory of epigenetic states. We previously demonstrated that the VIM1 (VARIANT IN METHYLATION 1) protein from the flowering plant Arabidopsis thaliana binds DNA that contains methylated cytosine and is required for complete methylation and compaction of centromeric DNA. In this study, we show that VIM1 works in concert with two related proteins, VIM2 and VIM3, to maintain cytosine methylation not only at centromeres but throughout the genome. VIM proteins act specifically in the DNA methylation pathway that targets CpG dinucleotides, which plants share with animals, rather than the plant-specific non-CpG methylation pathways. Loss of VIM1, VIM2, and VIM3 function also causes a reduction in transcriptional gene silencing at a variety of sequences, and leads to abnormal developmental phenotypes, including late flowering associated with loss of FWA gene silencing. Our results demonstrate that these three related VIM family proteins have overlapping functions in the MET1-mediated CpG methylation pathway.
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