DNA strand asymmetry generated by CpG hemimethylation has opposing effects on CTCF binding.
DNA strand asymmetry generated by CpG hemimethylation has opposing effects on CTCF binding.
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DOI：
10.1093/nar/gkad293
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发表时间：
2023-07-07
影响因子：
14.9
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中科院分区：
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CpG甲基化通常发生在两条DNA链上，对哺乳动物的发育和分化至关重要。直到最近，半甲基化（其中只有一条链被甲基化）被认为只是DNA合成过程中产生的短暂状态。CCCTC结合因子（CTCF）结合位点的一个子集被遗传性半甲基化的发现表明，半甲基化可能具有未知的生物学功能。在这里，我们表明，CTCF的结合是深刻地改变了DNA链甲基化和特定的CTCF结合基序。基序链上的CpG甲基化可以抑制CTCF结合高达7倍，而相对链上的甲基化可以刺激结合高达4倍。因此，半甲基化可以以链特异性方式改变结合高达28倍。在相对链上感测甲基化的机制需要CTCF锌指7和4内的两个关键残基V454和S364。与甲基化类似，基序链上的CpG羟甲基化可以抑制CTCF结合高达4倍。然而，相反链上的羟甲基化消除了刺激作用。因此，链特异性甲基化状态可以提供一种机制来解释CTCF介导的染色质相互作用的瞬时和动态性质。由半甲基化CpG二联体产生的不对称性对CTCF结合具有相反的影响。基序链上的甲基化抑制结合，而相对链上的甲基化刺激结合，导致两种半甲基化状态之间的28倍差异。用于感测相对链上的甲基化的机制需要CTCF锌指7和4内的缬氨酸454和丝氨酸364。
CpG methylation generally occurs on both DNA strands and is essential for mammalian development and differentiation. Until recently, hemimethylation, in which only one strand is methylated, was considered to be simply a transitory state generated during DNA synthesis. The discovery that a subset of CCCTC-binding factor (CTCF) binding sites is heritably hemimethylated suggests that hemimethylation might have an unknown biological function. Here we show that the binding of CTCF is profoundly altered by which DNA strand is methylated and by the specific CTCF binding motif. CpG methylation on the motif strand can inhibit CTCF binding by up to 7-fold, whereas methylation on the opposite strand can stimulate binding by up to 4-fold. Thus, hemimethylation can alter binding by up to 28-fold in a strand-specific manner. The mechanism for sensing methylation on the opposite strand requires two critical residues, V454 and S364, within CTCF zinc fingers 7 and 4. Similar to methylation, CpG hydroxymethylation on the motif strand can inhibit CTCF binding by up to 4-fold. However, hydroxymethylation on the opposite strand removes the stimulatory effect. Strand-specific methylation states may therefore provide a mechanism to explain the transient and dynamic nature of CTCF-mediated chromatin interactions. The asymmetry resulting from hemimethylated CpG dyads has opposing effects on CTCF binding. Methylation on the motif strand inhibits binding, whereas methylation on the opposite strand stimulates binding resulting in a 28-fold difference between the two hemimethylation states. The mechanism for sensing methylation on the opposite strand requires valine 454 and serine 364 within CTCF zinc fingers 7 and 4.
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DOI：
10.1093/bioinformatics/btq033
发表时间：
2010-03-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
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通讯作者：
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影响因子：
5.5
作者：
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DOI：
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发表时间：
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影响因子：
11.1
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DOI：
10.1073/pnas.1815005115
发表时间：
2018-12-18
影响因子：
11.1
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通讯作者：
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DOI：
10.1126/science.abn6583
发表时间：
2022-04-29
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
通讯作者：
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