Hemi-methylated DNA opens a closed conformation of UHRF1 to facilitate its histone recognition.
Hemi-methylated DNA opens a closed conformation of UHRF1 to facilitate its histone recognition.
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半甲基化 DNA 打开 UHRF1 的闭合构象以促进其组蛋白识别
DOI：
10.1038/ncomms11197
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发表时间：
2016-04-05
影响因子：
16.6
通讯作者：
Xu Y
中科院分区：
文献类型：
--
作者：
Fang J;Cheng J;Wang J;Zhang Q;Liu M;Gong R;Wang P;Zhang X;Feng Y;Lan W;Gong Z;Tang C;Wong J;Yang H;Cao C;Xu Y
UHRF1是维持DNA甲基化的重要表观遗传调控因子。UHRF1识别半甲基化DNA （hm-DNA）和组蛋白H3K9 （H3K9me3）的三甲基化，但其调控机制尚不清楚。本研究表明，UHRF1采用封闭构象，其中c -末端区域（Spacer）与串联Tudor结构域（TTD）结合并抑制H3K9me3识别，而set -and- ring相关结构域（SRA）与植物同源结构域（PHD）结合并抑制H3R2识别。Hm-DNA破坏分子内相互作用，促进TTD-PHD对H3K9me3的识别。Spacer还促进了UHRF1-DNMT1的相互作用，增强了SRA的hm- dna结合亲和力。当TTD-PHD与H3K9me3结合时，SRA-Spacer可能处于动态平衡状态：要么识别hm-DNA，要么招募DNMT1到染色质上。我们的研究揭示了URHF1调控H3K9me3和hm-DNA识别的机制。
UHRF1 is an important epigenetic regulator for maintenance DNA methylation. UHRF1 recognizes hemi-methylated DNA (hm-DNA) and trimethylation of histone H3K9 (H3K9me3), but the regulatory mechanism remains unknown. Here we show that UHRF1 adopts a closed conformation, in which a C-terminal region (Spacer) binds to the tandem Tudor domain (TTD) and inhibits H3K9me3 recognition, whereas the SET-and-RING-associated (SRA) domain binds to the plant homeodomain (PHD) and inhibits H3R2 recognition. Hm-DNA impairs the intramolecular interactions and promotes H3K9me3 recognition by TTD–PHD. The Spacer also facilitates UHRF1–DNMT1 interaction and enhances hm-DNA-binding affinity of the SRA. When TTD–PHD binds to H3K9me3, SRA-Spacer may exist in a dynamic equilibrium: either recognizes hm-DNA or recruits DNMT1 to chromatin. Our study reveals the mechanism for regulation of H3K9me3 and hm-DNA recognition by URHF1.