Multistate structures of the MLL1-WRAD complex bound to H2B-ubiquitinated nucleosome

Area of Science:

• Epigenetics and Gene Regulation
• Structural Biology
• Molecular Mechanisms of Transcription

Background:

• The Mixed Lineage Leukemia-1 (MLL1) complex regulates gene transcription via histone H3 lysine 4 (H3K4) methylation.
• This methylation is stimulated by histone H2B monoubiquitination.
• Previous structures of the MLL1-WRAD core complex (MLL1, WDR5, RbBp5, Ash2L, DPY30) showed variability in nucleosome docking and ambiguous regions.

Purpose of the Study:

• To determine the structure of the MLL1-WRAD complex bound to ubiquitinated nucleosomes.
• To elucidate the role of histone H2B ubiquitination in MLL1-WRAD assembly and activity.
• To provide a more complete structural model of the active MLL1-WRAD complex.

Main Methods:

• Integrated approach combining cryoelectron microscopy (cryo-EM).
• Mass spectrometry cross-linking (MSXL) to analyze complex assembly and interactions.
• Determination of multiple MLL1-WRAD complex states, including those with and without specific subunits.

Main Results:

• A detailed structural model of MLL1-WRAD bound to ubiquitinated nucleosomes was obtained.
• The model includes previously ambiguous regions of Ash2L and the DPY30 dimer.
• Four distinct states of MLL1-WRAD were resolved, revealing subunit assembly dynamics.
• Subunit docking differed significantly in the presence of H2B ubiquitination compared to unmodified nucleosomes.

Conclusions:

• Histone H2B ubiquitination favors the assembly of the active MLL1-WRAD methyltransferase complex.
• The study provides a comprehensive structural view of MLL1-WRAD and its regulation by ubiquitin.
• These findings advance our understanding of epigenetic mechanisms controlling gene transcription.