Nucleosomes containing methylated DNA stabilize DNA methyltransferases 3A/3B and ensure faithful epigenetic inheritance.
Nucleosomes containing methylated DNA stabilize DNA methyltransferases 3A/3B and ensure faithful epigenetic inheritance.
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DOI：
10.1371/journal.pgen.1001286
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发表时间：
2011-02-03
期刊：
影响因子：
4.5
通讯作者：
Liang G
中科院分区：
文献类型：
--
作者：
Sharma S;De Carvalho DD;Jeong S;Jones PA;Liang G
How epigenetic information is propagated during somatic cell divisions is still unclear but is absolutely critical for preserving gene expression patterns and cellular identity. Here we show an unanticipated mechanism for inheritance of DNA methylation patterns where the epigenetic mark not only recruits the catalyzing enzyme but also regulates the protein level, i.e. the enzymatic product (5-methylcytosine) determines the level of the methylase, thus forming a novel homeostatic inheritance system. Nucleosomes containing methylated DNA stabilize de novo DNA methyltransferases, DNMT3A/3B, allowing little free DNMT3A/3B enzymes to exist in the nucleus. Stabilization of DNMT3A/3B on nucleosomes in methylated regions further promotes propagation of DNA methylation. However, reduction of cellular DNA methylation levels creating more potential CpG substrates counter-intuitively results in a dramatic decrease of DNMT3A/3B proteins due to diminished nucleosome binding and subsequent degradation of the unstable free proteins. These data show an unexpected self-regulatory inheritance mechanism that not only ensures somatic propagation of methylated states by DNMT1 and DNMT3A/3B enzymes but also prevents aberrant de novo methylation by causing degradation of free DNMT3A/3B enzymes. Proper inheritance of DNA methylation patterns is essential for preserving cellular identity and preventing malignant cellular transformation. In mammals, DNMT3A/3B, the de novo methyltransferases, establish the DNA methylation patterns during development and then maintain them in co-operation with the maintenance methyltransferase, DNMT1, through cell divisions. However, the mechanisms by which DNMT3A/3B assist DNMT1 in faithful inheritance of methylation patterns in somatic cells while guarding against aberrant de novo DNA methylation are still unclear. In this study, we present a novel principle of enzyme regulation where the levels of the catalyzing enzymes, DNMT3A/3B, are determined by the level of their own enzymatic product, i.e. 5-methylcytosine itself. Through biochemical analyses, we have shown that binding of DNMT3A/3B to nucleosomes with methylated DNA stabilizes these proteins, enabling faithful propagation of methylation patterns through cell divisions. However, reduction in DNA methylation results in diminished nucleosome binding of DNMT3A/3B and subsequent degradation of the free DNMT3A/3B proteins. This novel self-regulatory inheritance mechanism not only ensures faithful somatic propagation of methylated states but also prevents aberrant de novo methylation by causing degradation of free DNMT3A/3B enzymes.
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影响因子：
3.7
作者：
Kondo Y;Shen L;Ahmed S;Boumber Y;Sekido Y;Haddad BR;Issa JP
通讯作者：
Issa JP
影响因子：
3.5
作者：
Huang, THM;Perry, MR;Laux, DE
通讯作者：
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影响因子：
64.8
作者：
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影响因子：
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作者：
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通讯作者：
Jones, PA
DOI：
10.1073/pnas.0604602103
发表时间：
2006-09-19
影响因子：
11.1
作者：
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通讯作者：
Liang, Gangning