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 regulatorsnotably,
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.