Molecular basis for histone H3 "K4me3-K9me3/2" methylation pattern readout by Spindlin1.
Molecular basis for histone H3 "K4me3-K9me3/2" methylation pattern readout by Spindlin1.
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Spindlin1 读出组蛋白 H3“K4me3-K9me3/2”甲基化模式的分子基础。
DOI：
10.1074/jbc.ra120.013649
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发表时间：
2020-12-04
期刊：
影响因子：
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通讯作者：
Li H
中科院分区：
文献类型：
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作者：
Zhao F;Liu Y;Su X;Lee JE;Song Y;Wang D;Ge K;Gao J;Zhang MQ;Li H
“阅读器”模块对组蛋白的识别是表观遗传调控的基本机制。先前的研究表明Spindlin 1是组蛋白H3 K4 me 3以及“K4 me 3-R8 me 2a”的阅读器，并促进rDNA或Wnt/TCF 4靶基因的转录。在这里，我们发现Spindlin 1也是组蛋白H3“K4 me 3-K9 me 3/2”二价甲基化模式的有效阅读器。量热滴定显示Spindlin 1和H3“K4 me 3-K9 me 3”肽之间的结合亲和力为16 nm，这比肽水平上的大多数其他组蛋白读出事件强一到三个数量级。结构研究表明，同时识别H3 K4 me 3和H3 K9 me 3/2的芳香口袋2和1的Spindlin 1，分别。表观基因组分析研究表明，Spindlin 1与H3 K4 me 3和H3 K9 me 3峰共定位在富含转录及其调控的生物过程的基因子集中。此外，Spindlin 1峰的分布主要与H3 K4 me 3相关，但与H3 K9 me 3无关，这表明Spindlin 1是异染色质区产生的H3 K4 me 3的下游效应子。总的来说，我们的工作引起了人们对Spindlin 1作为有效的H3“K4 me 3-K9 me 3/2”二价标记阅读器的有趣功能的关注，从而平衡了H3 K9 me 3/2富集区域中的基因表达和沉默。
Histone recognition by “reader” modules serves as a fundamental mechanism in epigenetic regulation. Previous studies have shown that Spindlin1 is a reader of histone H3K4me3 as well as “K4me3-R8me2a” and promotes transcription of rDNA or Wnt/TCF4 target genes. Here we show that Spindlin1 also acts as a potent reader of histone H3 “K4me3-K9me3/2” bivalent methylation pattern. Calorimetric titration revealed a binding affinity of 16 nm between Spindlin1 and H3 “K4me3-K9me3” peptide, which is one to three orders of magnitude stronger than most other histone readout events at peptide level. Structural studies revealed concurrent recognition of H3K4me3 and H3K9me3/2 by aromatic pockets 2 and 1 of Spindlin1, respectively. Epigenomic profiling studies showed that Spindlin1 colocalizes with both H3K4me3 and H3K9me3 peaks in a subset of genes enriched in biological processes of transcription and its regulation. Moreover, the distribution of Spindlin1 peaks is primarily associated with H3K4me3 but not H3K9me3, which suggests that Spindlin1 is a downstream effector of H3K4me3 generated in heterochromatic regions. Collectively, our work calls attention to an intriguing function of Spindlin1 as a potent H3 “K4me3-K9me3/2” bivalent mark reader, thereby balancing gene expression and silencing in H3K9me3/2-enriched regions.