More than half of the human proteome comprises intrinsically disordered regions (IDRs), which are critical to cellular processes and disease. Despite their importance, IDRs do not fold into predictable three-dimensional structures, which has caused them to remain poorly understood. Although these regions are highly dynamic, it is understood that they are governed by distinct non-random amino acid compositional biases and patterning termed “sequence grammars” that underlie their specialized functions. Recent work has quantified sequence grammars across the human proteome and revealed that the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex harbors exceptionally diverse grammars within its IDRs and is frequently mutated in cancer.
Building on these findings, this ASPIRE Award will explore how IDRs within mSWI/SNF complexes direct the formation of biomolecular condensates and influence genomic targeting, gene regulation, and oncogenic activity. By integrating computational, biophysical, biochemical, and genetic approaches, the project aims to define how sequence grammars govern condensate formation, protein–protein interactions, chromatin remodeling, and transcriptional programs in both normal and cancer-associated mutant states. These studies will yield a new framework for understanding how IDR grammars shape oncogenic chromatin regulation and condensate biology, with anticipated insights into cancer dependencies, therapeutic targets, and broadly applicable principles of disease biology.