Dissecting the precise role of H3K9 methylation in crosstalk with DNA maintenance methylation in mammals.
Dissecting the precise role of H3K9 methylation in crosstalk with DNA maintenance methylation in mammals.
复制标题
剖析 H3K9 甲基化在哺乳动物 DNA 维持甲基化串扰中的精确作用
DOI：
10.1038/ncomms12464
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发表时间：
2016-08-24
影响因子：
16.6
通讯作者：
Wong J
中科院分区：
文献类型：
--
作者：
Zhao Q;Zhang J;Chen R;Wang L;Li B;Cheng H;Duan X;Zhu H;Wei W;Li J;Wu Q;Han JD;Yu W;Gao S;Li G;Wong J
在哺乳动物中，目前尚不清楚DNMT 1介导的UHRF 1介导的DNA维持甲基化是否严格依赖于组蛋白H3 K9甲基化。在这里，我们已经产生了一个Uhrf 1敲入（KI）小鼠模型，专门取消H3 K9 me 2/3结合活性的Uhrf 1。同源Uhrf 1 KI小鼠是存活的和可生育的，并且在各种组织中表现出约10%的DNA甲基化降低。在体外，UHRF 1与半甲基化CpG的结合亲和力高于与H3 K9 me 2/3的结合，但与两种修饰的核小体结合时，UHRF 1与两种修饰的核小体的结合是协同的。我们还表明，核小体的定位影响UHRF 1的甲基化DNA的结合。因此，虽然我们的研究支持H3 K9甲基化在促进DNA甲基化中的作用，但它首次证明哺乳动物中的DNA维持甲基化在很大程度上独立于H3 K9甲基化。
In mammals it is unclear if UHRF1-mediated DNA maintenance methylation by DNMT1 is strictly dependent on histone H3K9 methylation. Here we have generated anUhrf1knockin (KI) mouse model that specifically abolishes the H3K9me2/3-binding activity of Uhrf1. The homozygousUhrf1KI mice are viable and fertile, and exhibit ∼10% reduction of DNA methylation in various tissues. The reduced DNA methylation occurs globally in the genome and does not restrict only to the H3K9me2/3 enriched repetitive sequences.In vitroUHRF1 binds with higher affinity to reconstituted nucleosome with hemi-methylated CpGs than that with H3K9me2/3, although it binds cooperatively to nucleosome with both modifications. We also show that the nucleosome positioning affects the binding of methylated DNA by UHRF1. Thus, while our study supports a role for H3K9 methylation in promoting DNA methylation, it demonstrates for the first time that DNA maintenance methylation in mammals is largely independent of H3K9 methylation.