Structural basis for COMPASS recognition of an H2B-ubiquitinated nucleosome

Area of Science:

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

Background:

• Histone H3 lysine 4 (H3K4) methylation is a key epigenetic mark associated with active gene transcription.
• This methylation is dependent on histone H2B mono-ubiquitination (H2B-Ub), a process involving trans-histone crosstalk.
• In yeast, the COMPASS complex, particularly its Set1 methyltransferase subunit, catalyzes H3K4 methylation.

Purpose of the Study:

• To determine the structural basis of COMPASS-mediated H3K4 methylation.
• To elucidate the mechanism by which H2B-Ub stimulates COMPASS activity.
• To understand the spatial arrangement of COMPASS on the nucleosome and its interaction with ubiquitin.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine the structure of the COMPASS subcomplex bound to a ubiquitinated nucleosome.
• Biochemical assays to assess H3K4 methyltransferase activity and stimulation by H2B-Ub.

Main Results:

• The cryo-EM structure of a six-protein core COMPASS subcomplex bound to a ubiquitinated nucleosome was determined.
• COMPASS spans the nucleosome, with distinct interaction sites for the nucleosome and H2B-Ub.
• Set1 undergoes significant structural rearrangements upon nucleosome and ubiquitin binding, including the formation of a helical structure by the RxxxRR motif that bridges interactions.

Conclusions:

• The structure provides a mechanistic framework for understanding how H2B ubiquitination stimulates H3K4 methylation by COMPASS.
• It highlights the importance of trans-histone crosstalk in regulating epigenetic modifications.
• The findings offer insights into the dynamic interactions governing gene transcription regulation.