State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Nature. 2019 Sep;573(7774):445-449. doi: 10.1038/s41586-019-1528-1. Epub 2019 Sep 4.
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. 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. 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. 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.
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——将组蛋白 H3 赖氨酸 4（H3K4）甲基化，并在造血、脂肪生成和发育过程中的转录调控中发挥关键且独特的作用。MLL 蛋白的 C 端催化 SET（Su(var.)3-9、增强子结合锌指蛋白和 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。目前对 MLL 活性的调控知之甚少，仅限于组蛋白 H3 肽的催化，而 H3K4 甲基标记如何沉积在核小体上则知之甚少。H3K4 甲基化受到组蛋白 H2B 赖氨酸 120 单泛素化（H2BK120ub1）的刺激，H2BK120ub1 是一种普遍存在的组蛋白 H2B 标记，可破坏染色质的紧缩并有利于开放染色质结构，但潜在的机制尚不清楚。本文报道了与人 MLL1 和 MLL3 催化模块相关的核小体核心颗粒的低温电子显微镜结构，这些结构包含 H2BK120ub1 或未修饰的 H2BK120。这些结构表明，MLL1 和 MLL3 复合物都与核小体的组蛋白折叠和 DNA 区域进行广泛接触；这使得容易接触到组蛋白 H3 尾巴，这对于 H3K4 的有效甲基化至关重要。H2B 缀合的泛素直接结合到 RBBP5 上，从而将 MLL1 或 MLL3 与核小体连接起来。MLL1 和 MLL3 复合物在 WDR5、RBBP5 和 MLL1（或相应的 MLL3）亚基之间的界面处显示出不同的结构组织，这解释了 WDR5 在调节两种酶活性方面的相反作用。这些发现改变了我们对核小体水平上 MLL 活性调节的结构基础的理解，并强调了核小体调节在组蛋白尾巴修饰中的关键作用。
