Structural basis of complex assembly and nucleosome recognition by the chromatin remodeling ncBAF complex

Area of Science:

• Molecular Biology
• Structural Biology
• Genetics

Background:

• BRG1/BRM-associated factor (BAF) complexes are crucial for transcription and genome organization via nucleosome repositioning.
• The human non-canonical BAF (ncBAF) complex differs from canonical BAF complexes by lacking ARID1/2 and specific binding modules, but includes BRD9 and GLTSCR1/GLTSCR1L.
• The assembly and nucleosome engagement mechanisms of ncBAF remain poorly understood.

Purpose of the Study:

• To elucidate the structural basis of ncBAF complex assembly and its interaction with nucleosomes.
• To understand how ncBAF compensates for the absence of canonical nucleosome-binding modules.
• To provide a structural framework for ncBAF's role in chromatin regulation and disease.

Main Methods:

• Cryo-electron microscopy (cryo-EM) to determine the structure of ncBAF bound to a nucleosome.
• Biochemical assays to assess complex assembly and function.
• Crosslinking mass spectrometry (XL-MS) to map subunit interactions.

Main Results:

• The ncBAF complex exhibits a three-module architecture: ATPase motor, repositioned actin-related protein (ARP) module, and a flexible Base module.
• ncBAF-specific subunits BRD9 and GLTSCR1L are not essential for complex assembly or remodeling.
• BCL7A directly interacts with the H2A-H2B acidic patch and H2A N-terminal tail, functionally replacing SMARCB1 in stimulating remodeling.

Conclusions:

• ncBAF reorganizes its modular structure to compensate for the lack of canonical nucleosome-binding components.
• BCL7A plays a key role in mediating ncBAF-nucleosome interactions and stimulating activity.
• The findings offer a structural understanding of ncBAF function in chromatin regulation, with implications for development and disease.