Structural basis of nucleosome recognition and modification by MLL methyltransferases

Area of Science:

• Epigenetics and Gene Regulation
• Structural Biology
• Molecular Mechanisms of Histone Modification

Background:

• Methyltransferases of the mixed-lineage leukaemia (MLL) family are essential for transcriptional regulation in development and cellular processes.
• The precise mechanisms by which MLL enzymes deposit H3K4 methylation marks onto nucleosomes, particularly in response to histone H2B ubiquitination, remain poorly understood.
• MLL proteins function as part of a complex with regulatory factors like WDR5, RBBP5, ASH2L, and DPY30.

Purpose of the Study:

• To elucidate the structural basis of MLL1 and MLL3 catalytic module interactions with nucleosomes.
• To understand how histone H2B mono-ubiquitination (H2BK120ub1) influences MLL activity and nucleosome binding.
• To reveal the distinct regulatory roles of WDR5 in MLL1 and MLL3 enzymatic activity.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was employed to determine high-resolution structures.
• Structures were obtained for human MLL1 and MLL3 catalytic modules bound to nucleosome core particles.
• Nucleosomes contained either unmodified histone H2B or H2BK120ub1.

Main Results:

• The MLL1 and MLL3 complexes exhibit extensive interactions with both the histone-fold and DNA of the nucleosome, facilitating access to the histone H3 tail for H3K4 methylation.
• The H2BK120ub1 mark directly interacts with RBBP5, a key component of the MLL complex, thereby orienting the enzyme-nucleosome association.
• Distinct structural organizations at the WDR5-RBBP5-MLL interface explain the opposing roles of WDR5 in regulating MLL1 versus MLL3 activity.

Conclusions:

• These findings provide unprecedented structural insights into how MLL enzymes are regulated at the nucleosome level.
• The study highlights the critical role of nucleosome structure, including histone modifications like H2BK120ub1, in directing histone-tail modification by MLLs.
• The differential regulation of MLL1 and MLL3 by WDR5 underscores the complexity of epigenetic control mechanisms.