Intrinsically Disordered Regions Control cBAF Condensation and Interactions

Intrinsically disordered regions (IDR) can functionally influence the dynamics and transcriptional activation of chromatin-bound proteins, with specific IDRs also being shown to play a critical role in liquid–liquid phase separation and the formation of biomolecular condensates. However, the function of IDRs in nuclear proteins, in which IDRs are enriched, is not fully understood, especially in the context of ATP-dependent chromatin remodelers. Patil, Strom, and colleagues sought to investigate the functions conferred by the IDRs present in ARID1A/B, which are subunits of the mammalian SWI/SNF chromatin remodeler cBAF and are frequently mutated in human cancers. Results showed that these IDRs, along with the ARID DNA binding domain (DBD), are dispensable for cBAF assembly but do confer condensation potential to cBAF that is enhanced by DNA binding and are also required for cBAF targeting, chromatin accessibility, and gene expression. Moreover, the IDR sequences and the ARID DBD of ARID1A were required for heterotypic interaction of cBAF with transcription factors and other transcriptional machinery needed for functional chromatin remodeling, with the ARID1A-specific IDR also being necessary for cBAF complex genomic targeting and protein interactions. Further analysis of ARID1A IDR sequence features revealed that condensate formation and heterotypic protein–protein interaction are distinct and separable aspects of the ARID1A IDR, with distinct, nonrandom “sequence grammars” enabling this uncoupling. Specifically, uniformly distributed tyrosine residues drive condensation, while alanine-glutamine-glycine stretches mediate partner interactions. Finally, evaluation of human disease–associated missense mutations that localize to the IDRs of ARID1A/B indicated that disease mutations are enriched in ARID1B as compared to ARID1A, and mutations in ARID1B IDR sequence blocks disrupt both cBAF genomic targeting and condensate formation. In summary, this study reveals that disordered regions in the cBAF complex confer condensation and heterotypic protein–protein interaction functions, which are both essential and independent features of cBAF-mediated gene-regulatory activities, as well as provides a potential framework that can be used to assign and characterize disease-associated mutations that fall within these regions.

Patil A, Strom AR, Paulo JA, Collings CK, Ruff KM, Shinn MK, et al. A disordered region controls cBAF activity via condensation and partner recruitment. Cell 2023 Oct 2 [Epub ahead of print].

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