Structural basis of nucleosome recognition and modification by MLL methyltransferases
Structural basis of nucleosome recognition and modification by MLL methyltransferases
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MLL 甲基转移酶识别和修饰核小体的结构基础
DOI：
10.1038/s41586-019-1528-1
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发表时间：
2019-09-19
期刊：
影响因子：
64.8
通讯作者：
Huang, Jing
中科院分区：
文献类型：
--
作者：
Xue, Han;Yao, Tonghui;Huang, Jing
混合谱系白血病（MLL）家族的甲基转移酶，包括MLL1、MLL2、MLL3、MLL4、SET1A和SET1B，负责组蛋白H3赖氨酸4（H3K4）位点的甲基化，在造血作用、脂肪生成及发育过程中的转录调控方面发挥着关键且独特的作用（1 - 6）。MLL蛋白的C端催化SET（Su(var.)3 - 9、zeste增强子和trithorax）结构域与一组常见的调节因子（WDR5、RBBP5、ASH2L和DPY30）相关联，以实现特定的活性（7 - 9）。目前对于MLL活性调控的认知仅限于其对组蛋白H3肽段的催化作用，而对于H3K4甲基化标记如何在核小体上沉积则知之甚少。H3K4甲基化受组蛋白H2B赖氨酸120位点的单泛素化（H2BK120ub1）刺激，H2BK120ub1是一种普遍存在的组蛋白H2B标记，它会破坏染色质的紧密结构，有利于形成开放的染色质结构，但其潜在机制仍不明确（10 - 12）。在此，我们报道了人源MLL1和MLL3催化模块与含有H2BK120ub1或未修饰H2BK120的核小体核心颗粒结合的冷冻电镜结构。这些结构表明，MLL1和MLL3复合物均与核小体的组蛋白折叠区和DNA区域有广泛接触；这使得它们能够轻易接近组蛋白H3的尾部，而这对于H3K4的高效甲基化至关重要。与H2B结合的泛素直接与RBBP5结合，从而确定了MLL1或MLL3与核小体之间的结合取向。MLL1和MLL3复合物在WDR5、RBBP5与MLL1（或相应的MLL3）亚基的界面处呈现出不同的结构组织形式，这解释了WDR5在调节这两种酶活性中发挥相反作用的原因。这些发现改变了我们对核小体水平上MLL活性调控结构基础的认识，并突出了核小体调控在组蛋白尾部修饰中的关键作用。
Methyltransferases of the mixed-lineage leukaemia (MLL) family-which include MLL1, MLL2, MLL3, MLL4, SET1A and SET1B-implement methylation of histone H3 on lysine 4 (H3K4), and have critical and distinct roles in the regulation of transcription in haematopoiesis, adipogenesis and development(1-6). The C-terminal catalytic SET (Su(var.)3-9, enhancer of zeste and trithorax) domains of MLL proteins are associated with a common set of regulatory factors (WDR5, RBBP5, ASH2L and DPY30) to achieve specific activities(7-9). Current knowledge of the regulation of MLL activity is limited to the catalysis of histone H3 peptides, and how H3K4 methyl marks are deposited on nucleosomes is poorly understood. H3K4 methylation is stimulated by mono-ubiquitination of histone H2B on lysine 120 (H2BK120ub1), a prevalent histone H2B mark that disrupts chromatin compaction and favours open chromatin structures, but the underlying mechanism remains unknown(10-12). Here we report cryo-electron microscopy structures of human MLL1 and MLL3 catalytic modules associated with nucleosome core particles that contain H2BK120ub1 or unmodified H2BK120. These structures demonstrate that the MLL1 and MLL3 complexes both make extensive contacts with the histone-fold and DNA regions of the nucleosome; this allows ease of access to the histone H3 tail, which is essential for the efficient methylation of H3K4. The H2B-conjugated ubiquitin binds directly to RBBP5, orienting the association between MLL1 or MLL3 and the nucleosome. The MLL1 and MLL3 complexes display different structural organizations at the interface between the WDR5, RBBP5 and MLL1 (or the corresponding MLL3) subunits, which accounts for the opposite roles of WDR5 in regulating the activity of the two enzymes. These findings transform our understanding of the structural basis for the regulation of MLL activity at the nucleosome level, and highlight the pivotal role of nucleosome regulation in histone-tail modification.