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

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.

溴结构域（Bromodomains，BRDs）是一类进化保守的结构域家族，是蛋白质乙酰化赖氨酸（Kac）残基的主要识别因子。近年来，大量含BRD的蛋白质被证实于多种生理环境中对转录调控发挥关键作用。这一点可通过多亚基mSWI/SNF染色质重塑复合物得到佐证：该复合物在5个不同亚基中共包含多达10个BRD，可实现对Kac信号的广泛整合，进而指导转录调控过程。鉴于转录失调可促进肿瘤发生，本研究旨在解析含BRD的亚基如何在分子层面参与mSWI/SNF复合物的功能发挥。本研究结合基因组编辑、功能蛋白质组学与细胞生物学技术，发现任意单个含BRD的mSWI/SNF亚基缺失仅会改变而非完全破坏各类mSWI/SNF复合物的组装。此外，本研究发现BRD7的表达下调在浸润性小叶癌中较为常见，且该下调可调控其同源蛋白BRD9的相互作用组。本研究证实，上述异常会加剧细胞对表观遗传调控因子抑制剂的敏感性——尤其是针对非mSWI/SNF蛋白BRD的抑制剂。本研究结果揭示了不同mSWI/SNF复合物之间的相互关联，及其对人类健康与疾病中转录调控的深远影响。本研究产生的质谱数据已提交至MassIVE与ProteomeXchange数据库，并获得标识符MSV000089357、MSV000089362及PXD033572。