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，它们在组蛋白H3第4位赖氨酸（H3K4）上负责甲基化，并且在造血、脂肪生成和发育的转录调节中具有关键和独特的作用。MLL蛋白的C末端催化结构域SET（Su(var.)3-9, enhancer of zeste and trithorax）与一组共同的调节因子（WDR5、RBBP5、ASH2L和DPY30）结合，从而来实现特定的活性。目前关于MLL活性调节的认知仅限于组蛋白H3肽段的催化，并且对H3K4甲基标记如何富集在核小体上的认知甚少。组蛋白H2B在赖氨酸第120位上的单泛素化（H2BK120ub1，这是一种普遍的组蛋白H2B标记）激活H3K4甲基化，破坏染色质压缩并有利于开放的染色质结构，但潜在的机制仍然未知。
Title: Structural basis of nucleosome recognition and modification by MLL methyltransferases
Author: Han Xue, Tonghui Yao, Mi Cao, Guanjun Zhu, Yan Li, Guiyong Yuan, Yong Chen, Ming Lei, Jing Huang
Abstract: Methyltransferases of the mixed-lineage leukaemia (MLL) familywhich include MLL1, MLL2, MLL3, MLL4, SET1A and SET1Bimplement methylation of histone H3 on lysine 4 (H3K4), and have critical and distinct roles in the regulation of transcription in haematopoiesis, adipogenesis and development16. 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 activities79. 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 unknown1012. 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.