Characterization of the Functional Interplay between the BRD7 and BRD9 Homologues in mSWI/SNF Complexes

Area of Science:

• Biochemistry
• Molecular Biology
• Epigenetics

Background:

• Bromodomains (BRDs) are protein modules that recognize acetylated lysine residues.
• BRD-containing proteins, particularly within mSWI/SNF complexes, are crucial for transcriptional regulation.
• Dysregulated transcription is a hallmark of oncogenesis.

Purpose of the Study:

• To investigate the molecular contributions of BRD-containing subunits to mSWI/SNF complex functions.
• To understand how alterations in BRD subunits affect transcriptional regulation and cancer.
• To explore the impact of BRD subunit loss on cellular sensitivity to epigenetic inhibitors.

Main Methods:

• Genome editing to create subunit deletions.
• Functional proteomics to analyze complex composition and interactions.
• Cellular biology assays to assess functional consequences.

Main Results:

• Loss of any single BRD-containing mSWI/SNF subunit partially altered mSWI/SNF complex integrity and function, but did not cause complete disruption.
• Downregulation of BRD7 was observed in invasive lobular carcinoma, affecting the interactome of BRD9.
• These alterations increased cellular sensitivity to inhibitors targeting bromodomains, including those on non-mSWI/SNF proteins.

Conclusions:

• Distinct mSWI/SNF complexes exhibit interconnections in their function.
• BRD-containing subunits play critical roles in integrating acetylation signaling for transcriptional control.
• Understanding these BRD-mSWI/SNF interactions offers insights into cancer pathogenesis and therapeutic strategies targeting epigenetic regulators.