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

Abstract

Bromodomains (BRDs) are a family of evolutionarily conserved domains that are the main readers of acetylated lysine (Kac) residues on proteins. Recently, numerous BRD-containing proteins have been proven essential for transcriptional regulation in numerous contexts. This is exemplified by the multi-subunit mSWI/SNF chromatin remodeling complexes, which incorporate up to 10 BRDs within five distinct subunits, allowing for extensive integration of Kac signaling to inform transcriptional regulation. As dysregulated transcription promotes oncogenesis, we sought to characterize how BRD-containing subunits contribute molecularly to mSWI/SNF functions. By combining genome editing, functional proteomics, and cellular biology, we found that loss of any single BRD-containing mSWI/SNF subunit altered but did not fully disrupt the various mSWI/SNF complexes. In addition, we report that the downregulation of BRD7 is common in invasive lobular carcinoma and modulates the interactome of its homologue, BRD9. We show that these alterations exacerbate sensitivities to inhibitors targeting epigenetic regulators─notably, inhibitors targeting the BRDs of non-mSWI/SNF proteins. Our results highlight the interconnections between distinct mSWI/SNF complexes and their far-reaching impacts on transcriptional regulation in human health and disease. The mass spectrometry data generated have been deposited to MassIVE and ProteomeXchange and assigned the identifiers MSV000089357, MSV000089362, and PXD033572.